PHYSIOLOGICAL REVIEWS   Vol. 79 No. 1 January 1999, pp. 73-98
Copyright ©1999 by the American Physiological Society

New Perspectives on Mechanisms Involved in Generating Epithelial Cell Polarity

CHARLES YEAMAN, KENT K. GRINDSTAFF, AND W. JAMES NELSON

Department of Molecular and Cellular Physiology, Beckman Center for Molecular and Genetic Medicine, Stanford University School of Medicine, Stanford, California

I. INTRODUCTION
II. SPATIAL CUES FOR EPITHELIAL CELL POLARITY: CELL ADHESION GENERATES ASYMMETRY AT THE CELL SURFACE AND THE AXES OF POLARITY
III. ASSEMBLY OF CYTOSKELETAL AND SIGNALING PROTEIN COMPLEXES AT SITES OF INTERACTION BETWEEN CELL ADHESION RECEPTORS AND EXTRACELLULAR CONTACTS
IV. CELL ADHESION INITIATES FORMATION OF STRUCTURES THAT SPECIFY DELIVERY AND RETENTION OF NEWLY SYNTHESIZED MEMBRANE PROTEINS
    A. Targeting Patches
    B. Membrane Skeletons
    C. Tight Junctions
V. TRANSLATION OF LOCALIZED SPATIAL INFORMATION INTO GLOBAL CHANGES IN CELL MORPHOLOGY
    A. Actin Reorganization
    B. Microtubule Reorganization
VI. SORTING AND TRANSPORT OF PROTEINS TO APICAL AND BASOLATERAL MEMBRANE DOMAINS REINFORCES AND MAINTAINS CELL SURFACE ASYMMETRY ESTABLISHED BY EXTRACELLULAR CONTACTS
VII. ROLE OF THE CYTOSKELETON IN VESICLE TRANSPORT
VIII. A HIERARCHY OF STAGES FOR ESTABLISHING CELL POLARITY
REFERENCES

	ABSTRACT

Top References

Yeaman, Charles, Kent K. Grindstaff, and W. James Nelson. New Perspectives on Mechanisms Involved in Generating Epithelial Cell Polarity. Physiol. Rev. 79: 73-98, 1999.  Polarized epithelial cells form barriers that separate biological compartments and regulate homeostasis by controlling ion and solute transport between those compartments. Receptors, ion transporters and channels, signal transduction proteins, and cytoskeletal proteins are organized into functionally and structurally distinct domains of the cell surface, termed apical and basolateral, that face these different compartments. This review is about mechanisms involved in the establishment and maintenance of cell polarity. Previous reports and reviews have adopted a Golgi-centric view of how epithelial cell polarity is established, in which the sorting of apical and basolateral membrane proteins in the Golgi complex is a specialized process in polarized cells, and the generation of cell surface polarity is a direct consequence of this process. Here, we argue that events at the cell surface are fundamental to the generation of cell polarity. We propose that the establishment of structural asymmetry in the plasma membrane is the first, critical event, and subsequently, this asymmetry is reinforced and maintained by delivery of proteins that were constitutively sorted in the Golgi. We propose a hierarchy of stages for establishing cell polarity.

	I. INTRODUCTION

Top Next References

Transporting epithelia form permeability barriers between two compartments in the body (e.g., ultrafiltrate and blood supply in the kidney) and vectorially transport ions and solutes between these compartments. These functions require a unique structural and functional organization of the cell. First, specialized cell adhesion complexes and cytoskeleton organizations are required to maintain cell-cell adhesion and cell attachment to the extracellular matrix (ECM). Second, the plasma membrane is divided into two structurally and functionally different domains, termed apical and basolateral. Each domain is comprised of a distinct subset of proteins, which regulate ion and solute transport across the epithelium. Differences in the distributions of membrane proteins between apical and basolateral plasma membrane domains are maintained by protein sorting from intracellular compartments and selective retention in the membrane (298).

Generally, epithelial cell polarity has been viewed from the standpoint of protein sorting in the trans-Golgi network (TGN) and endosomes (218, 301). For over 20 years (300, 302), it has been known that apical and basolateral proteins are sorted into distinct TGN-derived transport vesicles that traffic to different membrane domains. The accepted view is that this sorting event is a specialized process in polarized cells and is the basis for generating cell surface polarity (327). However, recent results indicate that sorting of apical and basolateral proteins in the TGN is a constitutive process, occurring in nonpolarized cells such as fibroblasts as well as polarized epithelial cells (244, 390). Moreover, membrane proteins in resting fibroblasts are not segregated into distinct membrane domains, despite sorting in the TGN, in contrast to their highly organized distributions in polarized epithelial cells. Therefore, additional processes must be involved in establishing and maintaining membrane domains in polarized epithelial cells.

In this review, we highlight the contributions of two processes that occur at the plasma membrane and that are critical for generating membrane asymmetry, namely, vesicle docking/fusion and selective protein retention. We also consider each of these processes in the broader context of how membrane polarity is generated de novo. We focus on the role of spatial cues at the cell surface in triggering a molecular cascade that establishes cell polarity. We propose that this cascade is initiated by a combination of extrinsic spatial cues mediated by cell-cell and cell-substratum adhesion. These cues physically and molecularly define contacting and noncontacting cell surfaces, which are the precursors of basolateral and apical membrane domains, respectively. These spatial cues initiate localized assembly of specialized cytoskeletal and signaling protein complexes at the contacting membrane, which position other cytoskeletal complexes and protein sorting compartments (TGN, endosomes) in the cytoplasm relative to the spatial cues. Subsequently, protein sorting from these compartments to the cell surface reinforces and maintains the structural and functional specialization of these membrane domains.

	II. SPATIAL CUES FOR EPITHELIAL CELL POLARITY: CELL ADHESION GENERATES ASYMMETRY AT THE CELL SURFACE AND THE AXES OF POLARITY

Top Previous Next References

We propose that the generation of epithelial cell polarity begins with the establishment of physical and molecular asymmetry at the cell surface (see Fig. 1). Single epithelial cells in suspension culture, in which there is neither cell-cell nor cell-substratum contact, exhibit nonpolarized distributions of marker proteins of the apical and basolateral membrane domains (299, 371). Extracellular contacts, either between a single cell and the ECM or between two cells in the absence of matrix, initiate the segregation of proteins into contacting and noncontacting (free) surface domains. Cell-cell and cell-substratum contacts are specified by adhesion receptor proteins. Adhesion between epithelial cells is mediated principally by E-cadherin, a member of the Ca²⁺-dependent cadherin superfamily of adhesion receptors (reviewed in Ref. 179). Cell adhesion to ECM is mediated by the integrin superfamily of adhesion receptors (reviewed in Ref. 162). We propose that interactions between these receptors and their corresponding extracellular ligands constitute the primary spatial cues that mark the contact sites on the plasma membrane and serve to distinguish these sites from noncontacting sites. Data supporting this proposal are summarized in section II.

View larger version (32K): [in this window] [in a new window]   FIG. 1.   Cell adhesion initiates cellular asymmetry and establishes axes of polarity. Schematic representation of cellular reorganization that occurs after establishment of cell-cell and/or cell-substrate adhesion (see text for details). Establishment of cell adhesion contacts either between cells or with extracellular matrix (ECM) leads to establishment of distinct cellular morphologies. As discussed in text, cell-cell or cell-substrate adhesion is sufficient to generate an initial level of cellular asymmetry that is oriented with respect to noncontacting and contacting membranes. However, both adhesion events are required to establish and maintain overall molecular and structural asymmetry characteristic of polarized epithelial cells (see text for details). TV, transport vesicles; N, nucleus; MTOC, microtubule organizing center; MT, microtubule; MF, microfilament; Ap-endo, apical endosome; Bl-endo, basal endosome.

Cell-cell adhesion is required to restrict the localization of basolateral membrane proteins in the plasma membrane. This was first demonstrated by examining the distributions of endogenous marker proteins of the basolateral membrane domain in Madin-Darby canine kidney (MDCK) monolayers cultured at low cell density (14, 136, 254) or after extracellular calcium depletion (266, 363) to reduce cadherin-dependent cell-cell adhesion. Under these culture conditions, cells fail to form extensive cell-cell contacts, and despite cell attachment to the ECM, basolateral membrane proteins are randomly localized on the cell surface. Even in the absence of cellular contact with the ECM, cell-cell adhesion is sufficient to initiate the segregation of both apical and basolateral membrane proteins into different membrane domains. Small clusters of MDCK cells grown in suspension restrict the budding of influenza virus to the free surface, whereas vesicular stomatitis virus (VSV) budding occurs only along the contacting surface (299). Cell-cell adhesion also initiates asymmetry in endogenous plasma membrane proteins. Adhesion between two cells in suspension is sufficient to cause an endogenous apical membrane protein (gp135) to localize to the free surface domain facing the culture medium and two basolateral proteins (Na⁺-K⁺-ATPase and E-cadherin) to localize to the cell-cell contacting membranes (371). The central role that E-cadherin plays in specifying membrane asymmetry was demonstrated by expressing E-cadherin ectopically in L-cell fibroblasts (229). Normally, these cells lack surface domains that are characteristic of polarized epithelial cells. However, expression of E-cadherin caused the redistribution of certain endogenous proteins (e.g., Na⁺-K⁺-ATPase, fodrin) to cell-cell contacts similar to their distributions after cell-cell adhesion in polarized epithelial cells.

Cell adhesion to ECM, which is mediated by the integrin superfamily of adhesion receptors, is also important for generating membrane asymmetry. Upon attachment of single MDCK cells to the ECM, several marker proteins of the apical membrane become rapidly localized to the free cell surface and excluded from the membrane in contact with the substratum, and apical microvilli form on the contact-free surface (266, 363). This is in contrast to basolateral membrane proteins, which remain randomly distributed on both membrane domains (254).

Cell adhesion to the ECM is particularly important for organizing the apicobasal axis of polarity. This axis defines the orientation of apical and basolateral membrane domains relative to the biological compartments separated by the epithelium, and hence the direction of ion and solute transport. An important indicator of the apicobasal polarity axis is the position of the tight junction at the apicolateral membrane boundary. As noted above, epithelial cell aggregates grown in suspension culture (i.e., in the presence of cell-cell contacts) form different membrane domains relative to the contact site between cells. Although the tight junction location would be expected at the boundary of the apical (outside surface) and lateral (cell-cell contact) membrane domains, the tight junction-associated protein ZO-1 is localized all along the cell-cell contacts similar to E-cadherin (371). After cells have accumulated an endogenously secreted ECM (type IV collagen, laminin) in the center of the cyst, the location of the tight junction becomes restricted to the apicolateral membrane boundary. Thus the apicobasal axis of polarity is established in these cell aggregates only after an ECM accumulates on one side of the cells. This conclusion is further supported by the observation that the establishment of an apico-basal axis is blocked in these cultures by addition of cis-OH-proline, an inhibitor of collagen secretion (371). Another example of the importance of ECM location in organizing the apicobasal axis of polarity is during reversal of polarity after cysts formed in suspension culture are transferred into a collagen gel matrix (372). Apical membrane proteins are internalized from the outside surface (now in contact with the collagen gel) and degraded. A new apical surface forms on the luminal surface and the tight junction relocates to the new apicolateral membrane boundary (372).

These changes in the axis of polarity, induced by the orientation of ECM relative to different epithelial cell surfaces, are mediated by integrins. For example, the reversal of polarity induced by placing suspension-grown cysts in collagen matrix is inhibited by antibodies against the ₁-integrin subunit, suggesting that the collagen receptor plays a central role in establishing the apicobasal axis (268). Moreover, when expression of ₂₁-integrin is inhibited by expression by ₂-integrin subunit antisense RNA, MDCK cells fail to establish an apicobasal axis and form only small rudimentary cysts lacking a central lumen (309). Further evidence for the central role that integrins play in establishing the apicobasal axis of polarity has been provided by studies on tubulocyst formation by MDCK cell monolayers when overlaid with type I collagen gel. Upon contact of the apical cell surface with collagen, the apical plasma membrane protein gp135 is rapidly internalized and subsequently reappears at sites of lateral membrane cell-cell contact where a microvilli-lined apical luminal compartment eventually forms (265). The ₂₁-integrin is primarily localized on the basolateral membrane domain (320), but remodeling of the cell surface in response to collagen is dependent on expression of a relatively minor amount of ₂₁-integrin on the apical plasma membrane. Antibodies against either the ₂- (322) or ₁-integrin subunits (322, 392) inhibit endocytosis of apical plasma membrane and formation of the apical lumen. Furthermore, a clone of MDCK cells that does not express ₂₁-integrin on the apical plasma membrane does not bind the type I collagen gel and fails to form tubulocyts (392).

Cell contact with specific ECM proteins can also direct the polarized distribution of specific plasma membrane proteins in the absence of a complete remodeling of cellular architecture. One example is hensin, a 230-kDa ECM protein secreted by intercalated epithelial cells (6, 340, 357). Cells plated on a substrate containing hensin express an "alpha" phenotype characterized by active endocytosis at the apical plasma membrane and express the anion exchanger AE1 on the basolateral membrane and H⁺-ATPase on the apical domain (357). In contrast, cells plated on substrates lacking hensin reverse the polarity of both proteins and do not undergo apical endocytosis (357). Together, these results strengthen the conclusion that although cell-cell adhesion can initiate the segregation of proteins within the plane of the membrane, cell adhesion to ECM is required to provide a spatial cue for the establishment of the axis of polarity in polarized epithelial cells.

	III. ASSEMBLY OF CYTOSKELETAL AND SIGNALING PROTEIN COMPLEXES AT SITES OF INTERACTION BETWEEN CELL ADHESION RECEPTORS AND EXTRACELLULAR CONTACTS

Top Previous Next References

How are spatial cues from extracellular contacts propagated through cell adhesion receptors to the rest of the cell surface and cell interior? Integrin- and cadherin-mediated adhesion induce localized assembly of networks of specialized cytoskeletal and signaling proteins at contacting membranes, which direct both local and global changes in the organization of the cell surface and the secretory apparatus (reviewed in Refs. 16, 54, 70, 276, 387).

The actin cytoskeleton is associated with both cadherin and integrin adhesion receptors. We propose that these interactions serve to reinforce the spatial cues provided by extracellular contacts by several mechanisms. First, associations between adhesion receptors and an actin-based cytoskeleton strengthen cell-cell and cell-ECM contacts. Second, localized cytoskeleton assemblies serve as a scaffold for recruitment and binding of signaling proteins that further define different membrane domains. Third, these interactions promote the assembly of structures that physically restrict intermixing of newly synthesized apical and basolateral membrane proteins. Each of these mechanisms is described in separate sections below.

Integrins bind to three cytoskeletal proteins in vitro: -actinin (271), talin (150), and paxillin (195). Conserved sequences in the cytoplasmic domains of integrin -subunits mediate each of these associations (195, 272) and contribute to integrin localization at cell-ECM contact sites (195, 292). -Actinin is a homodimer that binds and cross-links actin. Furthermore, -actinin binds vinculin (369), which is another actin-binding protein that also binds talin (44), paxillin (352), and tensin (171). Thus actin filaments may be linked to integrins directly through -actinin and talin or indirectly via vinculin and tensin. These assemblies of integrins with associated structural proteins are thought to be essential for stabilizing cell-ECM adhesion and regulating cell shape and polarity. Support for this notion was provided by studies in which fibroblasts were microinjected with proteolytic fragments corresponding to either the integrin- or actin-binding domains of -actinin (279). Both fragments caused stress fibers and focal contacts to reversibly disassemble, presumably by interfering with the activity of endogenous -actinin or associated proteins. Interestingly, mice lacking tensin develop large cysts in proximal kidney tubules resulting from weakened cell-ECM contacts and loss of cell polarity (200).

Engagement and clustering of integrins induces the assembly of a network of signaling proteins that transmit spatial information from the cell-ECM contact site to the interior of the cell (54, 70, 233, 276, 387). Integrin-ECM binding promotes rapid tyrosine phosphorylation of several proteins (45, 55, 259, 283). One of these proteins is focal adhesion kinase (FAK) (183, 198, 315). Focal adhesion kinase is a tyrosine kinase that localizes to focal adhesions through a carboxy-terminal focal adhesion targeting (FAT) domain (137) that partially overlaps with a paxillin-binding motif (138). Focal adhesion kinase serves to recruit several other signaling proteins to contact sites, including nonreceptor tyrosine kinases (e.g., Src, Fyn, and Csk) (58, 123, 234, 386), components of the RAS-MAP kinase pathway (e.g., SOS and Grb2) (234), as well as GTP-binding proteins (e.g., rho) (234) and associated proteins (139). Although the molecular interactions between integrins, FAK, and several other signaling proteins are well documented, the precise function of each of these associations in orchestrating changes in cell morphology is less clear. Overexpression of a dominant-negative construct containing the FAT domain results in displacement of FAK from focal adhesions and a concomitant decrease in tyrosine phosphorylation of FAK, paxillin, and tensin (111). However, these cells still assemble focal adhesions, although the rate at which they do so is reduced. Furthermore, cells lacking FAK are able to form normal focal adhesions (166). It is possible that FAK-related kinases could still be functioning in these cells, however. In contrast, a signaling pathway that is independent of FAK involves activation of rho and myosin light-chain phosphorylation (53). These events increase contractility and, together with integrin binding to ECM proteins, appear to be required for formation of focal adhesions and changes in cell morphology (43, 151).

Cadherin-mediated cell adhesion also results in localized assembly of cytoskeletal and signaling networks. A family of related cytoplasmic proteins, termed -catenin, plakoglobin, and p120^CAS, bind tightly to the cytoplasmic domain of cadherins (227, 273, 334). -Catenin and plakoglobin link cadherins to -catenin (1, 141), which can bind to and bundle F-actin filaments (294). However, -catenin and plakoglobin form distinct complexes with E-cadherin (140) and likely serve distinct functions, since plakoglobin does not appear to be involved in E-cadherin-mediated early cell-cell contacts (4). -Actinin is also a component of the cadherin/catenin complex and may provide an additional link between the complex and actin filaments (182, 258). The requirement for these associations in stabilizing cell-cell contacts was demonstrated by expressing E-cadherin constructs that either contained or lacked the cytoplasmic domain in L-cell fibroblasts (245, 246, 273). Cells expressing full-length E-cadherin formed stable cell-cell contacts, whereas cells expressing the truncated protein did not. In addition to strengthening cell-cell contacts, these associations serve to recruit signaling molecules to sites of cell-cell adhesion (reviewed in Refs. 1, 16). Tyrosine kinases (e.g., c-fyn and c-src) (351), kinase substrates (e.g., p100/120) (5, 323, 334), and tyrosine phosphatases (e.g., PTPµ, PTP-LAR) (30, 187) have been localized to cell-cell contacts, but an understanding of their functions in signaling at these sites is currently less well developed than at integrin-based adhesion sites.

	IV. CELL ADHESION INITIATES FORMATION OF STRUCTURES THAT SPECIFY DELIVERY AND RETENTION OF NEWLY SYNTHESIZED MEMBRANE PROTEINS

Top Previous Next References

Thus far, we have discussed how cell surface asymmetry is initiated by extrinsic spatial information provided by cell-cell and cell-ECM adhesion, and how this information is interpreted by adhesion receptors and transmitted to the cell interior by complex assemblies of cytoskeletal and signaling proteins. We propose that an early consequence of this spatial signaling is the generation of three types of membrane-associated structures that serve to reinforce membrane asymmetry by ensuring that newly synthesized membrane proteins are targeted to and retained in the appropriate membrane domain. These structures are 1) targeting patches, which specify docking and fusion of transport vesicles carrying either apical or basolateral membrane proteins; 2) membrane skeletons, which direct the retention and accumulation of specific proteins in different membrane domains; and 3) tight junctions, which provide a physical barrier at the boundary between the apical and lateral membrane domains, thereby preventing the intermixing of membrane proteins as well as lipids in the outer leaflet of the bilayer. Each of these structures is discussed individually in sections IVA-C.

Little is known about molecular interactions between TGN-derived transport vesicles and the plasma membrane of polarized epithelial cells. The SNARE hypothesis has provided a conceptual framework to begin characterizing the mechanisms involved (308). This model postulates that correct pairing of addressing proteins on the transport vesicle (termed v-SNAREs) with cognate receptors on the target membrane (termed t-SNAREs) determines the specificity of vesicle docking and fusion (46, 332). Vesicle-target membrane fusion also requires the activity of an ATPase, N-ethylmaleimide-sensitive fusion protein (NSF) (23, 206), and soluble NSF attachment proteins (SNAP) (56, 375). The SNAREs were identified as membrane-anchored receptors for SNAP (332, 333, 379, 381).

Vesicle-associated membrane proteins, synonymously referred to as VAMP-1 (349) and VAMP-2 (79), or synaptobrevin 1 (18) and synaptobrevin 2 (338), are the founding members of a growing family of related v-SNAREs (129, 130, 207, 230, 247, 274). These are small (~18 kDa), type II membrane proteins that have single carboxy-terminal transmembrane domains and most of their mass extending into the cytoplasm. Syntaxins, SNAP-25, and related proteins comprise an extended family of t-SNAREs defined by a conserved 60-amino acid "t-SNARE" homology domain (377). Syntaxins are type II membrane proteins, ~35 kDa in size, and occupy distinct cellular compartments (20, 21). As with the v-SNAREs, the list of syntaxin-related proteins is constantly growing (25, 26, 65, 129, 130, 157, 168). The SNAP-25 and related proteins (23-25 kDa) (33, 47, 51) are cytoplasmically oriented proteins that are anchored to the membrane by palmitoyl groups attached to central cysteine residues (366).

Endogenous t-SNAREs have polarized distributions in several epithelial cell types, including hepatocytes (94), enterocytes (71), gastric parietal cells (48, 282), renal collecting duct cells (90, 91, 170, 208, 209, 257), and pancreatic acinar cells (31, 99-102). In addition, exogenously expressed syntaxin isoforms have distinct distributions in polarized MDCK cells (203). Syntaxin 3 has been found primarily on the apical plasma membrane in MDCK cells (203), enterocytes (71), and hepatocytes (94) as well as on tubulovesicles (282) and zymogen granules (99) that will fuse with apical plasma membrane during regulated secretion in gastric parietal cells and pancreatic acinar cells, respectively. In contrast, syntaxin 4 is predominantly expressed on the basolateral membrane domain of MDCK cells (203), hepatocytes (94), and pancreatic acinar cells (99). Interestingly, a reversed polarity of these two syntaxin isoforms has been reported in renal collecting duct epithelia (208, 209). A ubiquitously expressed homolog of SNAP-25, SNAP-23, is expressed primarily on the basolateral membrane domain in rat pancreatic acinar cells (102) but is nonpolarized in MDCK and Caco-2 cells (104, 204).

Because t- and v-SNARE components have distinct polarized distributions in several epithelial cell types, it has been suggested that these proteins serve to specify the correct delivery of transport vesicles to apical and basolateral membrane domains (203, 376). However, this conclusion is almost certainly an oversimplification. First, although syntaxin isoforms are differentially distributed between distinct plasma membrane domains, their localizations are not restricted to a single membrane domain, and their expression patterns clearly overlap (94). Second, it has been suggested that exocytosis at the apical membrane domain is independent of SNAREs (165). Treatment of permeabilized MDCK cells with either tetanus toxin or botulinum neurotoxin serotype F, which cleave VAMP-1 and -2 and cellubrevin (196, 228), significantly reduced the efficiency of VSV G protein transport to the basolateral membrane but had no inhibitory effect on delivery of influenza virus hemagglutinin (HA) to the apical membrane (165). This result suggested that v-SNAREs are not required for apical secretion. It was also proposed that a novel mechanism, employing annexin XIIIB, is required for transport vesicle fusion with the apical plasma membrane (83). However, the possibility remains that a VAMP homolog that is insensitive to toxin cleavage is required for transport to the apical plasma membrane. This possibility is bolstered by the recent identification of a toxin-insensitive VAMP (TI-VAMP) in Caco-2 cells, which forms a complex with the apical t-SNARE syntaxin 3 and SNAP-23 (104). However, a function for TI-VAMP in apical transport has not yet been demonstrated.

The conclusion that apical exocytosis is independent of SNAREs is also based on the finding that neither NSF nor -SNAP appears to be required for apical transport of influenza HA (165). Several anti-NSF antibodies, when added to permeabilized MDCK cells, reduced the efficiency of VSV G protein delivery to the basolateral plasma membrane but had no effect on apical delivery of HA. A trivial explanation for this result is that an NSF homolog not recognized by these antibodies mediates fusion at the apical membrane domain (376). We suggest an alternative explanation, in which both NSF and -SNAP are required before vesicle docking and fusion with the apical plasma membrane. It is possible that NSF and -SNAP act to prime v- and t-SNAREs on the plasma membrane and on nascent apical transport vesicles during incubation at 19.5°C, before cell permeabilization. If true, then fusion of post-Golgi transport vesicles with the apical plasma membrane would occur by a mechanism analogous to yeast vacuolar fusion (121, 221, 256, 355). Thus, although the permeabilized cell transport assay does reveal differences in the mechanisms of vesicle docking and fusion at the apical and basolateral membrane domains, the protein components (i.e., NSF and -SNAP) involved in docking and fusion need not be distinct.

Although no evidence for the involvement of v- or t-SNAREs in constitutive transport from the TGN to the apical plasma membrane has been reported, both regulated apical secretion and apical secretion from endosomes (transcytosis) are dependent on SNAREs. Vesicle-associated membrane protein-2 is required for regulated apical secretion in pancreatic acinar cells (100), as well as fusion events responsible for vasopressin-stimulated aquaporin-2 trafficking to the apical membrane domain in the kidney papilla (170). Furthermore, transcytotic delivery of polymeric immunoglobulin receptors (pIgR) in MDCK cells is reduced by treatments that inhibit the functions of SNAP-23 and NSF (8, 204). This result is consistent with the localization of syntaxin 3 to the apical plasma membrane and endosomes in hepatocytes (94) and enterocytes (71), two cell types that rely on the transcytotic pathway for delivery of newly synthesized proteins to the plasma membrane (154, 190, 215).

Although evidence that SNARE complexes determine vesicle/target membrane fusion is strong, it is unclear whether interactions between cognate v- and t-SNAREs are sufficient to specify the site of vesicle docking with the target membrane. Much of the work on SNARE interactions has focused on events at the synapse, where synaptic vesicles are generated from a local endosome and are predocked at the synaptic membrane (reviewed in Refs. 47, 68). In most other cell types, post-TGN transport vesicles must traffic relatively long distances to their target membrane. Such is the case for vesicle delivery during bud formation in S. cerevisiae. During the cell cycle, the mother cell forms a new daughter cell bud through asymmetric growth of the plasma membrane and cell wall (115). Bud formation requires directed delivery of post-TGN transport vesicles from the mother to the daughter cell. Significantly, docking/fusion of these transport vesicles is restricted to a small region of the plasma membrane at the tip of the growing bud. If t-SNAREs alone specify transport vesicle docking with the bud tip, they should have a distribution that is restricted to that site. However, the plasma membrane t-SNARE, Sso1/2, and Sec9 are distributed uniformly over the mother cell and bud plasma membranes (33). Similarly, in neurons, syntaxin 1 and SNAP-25 have uniform distributions along the length of the axon, although the sites of synaptic transmission are restricted (103, 106). These results suggest that v- and t-SNAREs define a set of membranes that have the capacity to fuse, but that other proteins are required to define the site at which fusion occurs.

How are the sites of vesicle docking and fusion with plasma membrane selected? This is a matter of some speculation. It could be that t-SNAREs must be activated before fusion, perhaps by associating with certain proteins or dissociating from other proteins, to facilitate interactions with v-SNAREs (307). These accessory proteins could be restricted to sites of fusion. Alternatively, t-SNAREs may be competent for fusion everywhere on the plasma membrane, but other structures such as microtubules, actin, or septin filaments direct vesicles only to sites where fusion occurs (3). Apart from the question of how vesicle docking and fusion is controlled is the question of where targeting patches are located. Insight into each of these questions is gained by considering other proteins that play a role in vesicle docking and fusion.

One set of proteins that may control SNARE function includes homologs of S. cerivisiae Sec1, Drosophila melanogaster Rop, and Caenorhabditis elegans Unc-18 proteins. Initially identified as brain-specific syntaxin-binding proteins (105, 127, 286), isoforms of these 68-kDa proteins are ubiquitously expressed (128, 342). One isoform appears to be enriched at the apical plasma membrane of polarized epithelial cells (293). Mammalian Unc-18 homologs (Munc-18) lack membrane-spanning domains but may be recruited from the cytosol to the plasma membrane by association with syntaxins (286, 293). Munc-18a (also known as n-sec1/rb-sec1) and Munc-18b bind syntaxins 1a, 2, and 3 (128, 285), whereas Munc-18c binds syntaxins 2 and 4 (341). These in vitro binding studies reveal affinities in the nanomolar range (285, 341), although the complexes appear to be unstable in vivo (106). Interest in Munc-18 isoforms stems from the finding that Munc-18 binding to syntaxin inhibits syntaxin binding to SNAP-25 and VAMP (285). Therefore, Munc-18 proteins could regulate vesicle fusion by controlling the ability of syntaxins to interact with other components of the SNARE complex. A further level of control likely involves regulation of Munc-18/syntaxin binding by phosphorylation (95, 142), or Munc-18 binding proteins such as Mints (269) and DOC2 proteins (367). Regulatory proteins, such as Mints, may be restricted to sites of vesicle docking and fusion through interactions with specific plasma membrane proteins via PDZ domains (269).

A second set of proteins required for transport vesicle docking and fusion with the plasma membrane consists of a family of small GTP-binding proteins related to the yeast Ypt1/Sec4 proteins (260). Sec4p is present on post-Golgi transport vesicles and plasma membrane (114), and these vesicles accumulate in the daughter cell bud adjacent to the bud tip in sec4 mutants (312). A closely related mammalian homolog, rab8, is present on TGN-derived basolateral transport vesicles and on the basolateral membrane domain of polarized MDCK cells (155). Perturbation of rab8 function in permeabilized MDCK cells caused a significant reduction in the efficiency of vesicle transport to the basolateral but not the apical plasma membrane domain (155). Therefore, Sec4, rab8, and closely related proteins such as rab10 (52) and rab13 (391) are likely to be involved in vesicle docking and fusion with the plasma membrane. Although the precise role of these proteins is unclear, they have been proposed to potentiate the binding of v- and t-SNAREs (307, 331). Therefore, these proteins could be key regulators of either the timing or localization of vesicle fusion. Interestingly, both rab8 and rab13 are enriched on the plasma membrane at the apical junctional complex, which includes the tight junction and adherens junctions (155, 391). Furthermore, rab3B, an isoform of a brain-specific protein involved in synaptic vesicle fusion, also has a very restricted distribution at the tight junction (374). Disruption of cell-cell contacts results in redistribution of both rab3B and rab13 from the plasma membrane to the cytoplasm, indicating that the restricted distribution of these proteins is dependent on cell-cell contact (374, 391).

Although the rab proteins are likely to be involved in regulating vesicle docking and fusion, they are vesicle-associated proteins and therefore cannot, by themselves, mark a site on the plasma membrane for vesicle docking. It is true that certain rab proteins, such as rab3B, rab8, and rab13, are enriched on the plasma membrane at the tight junction (see above). However, it is not known whether these proteins are recruited to targeting patches before transport vesicles or if they are carried to exocytic sites on the vesicles themselves. We propose that rab3B, rab8, and rab13 are deposited at the apical junctional complex after vesicle docking and fusion at this site (see below). Steady-state localization of rab proteins at the apical junctional complex may result from slow removal from the plasma membrane relative to the rate of vesicle fusion.

A spatial landmark for vesicle docking and fusion must have the property that it is restricted to sites of exocytosis on the plasma membrane before arrival of transport vesicles. A further requirement for a spatial landmark involved in establishing plasma membrane domains during development of epithelial cell polarity is that the proteins that constitute the landmark should become spatially restricted after initiation of cell-cell or cell-ECM contact. Recent work from our laboratory indicates that a multiprotein complex consisting of mammalian homologs of the yeast Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, and Exo70 gene products meets these criteria (118). In yeast, this protein complex (termed the "exocyst"; Ref. 343) is present on the plasma membrane and is restricted to sites of active exocytosis, including the tips of growing buds and the motherbud neck of large-budded cells (87, 344). Recently, mammalian homologs of Sec5, Sec6, Sec8, Sec10, Sec15, and Exo70 have been identified in neurons (119, 133, 175, 348). Similar to yeast, these proteins are present in a large complex in neurons and MDCK cells (118, 152). In single MDCK cells in contact with the substratum, the Sec6/8 complex is diffusely distributed in the cytosol but is rapidly recruited (half-life, ~3-6 h) to the plasma membrane to sites of cell-cell contact after the induction of calcium-dependent cell adhesion (118). In early contacting cells, the Sec6/8 complex is codistributed with E-cadherin and the tight junction-associated protein ZO-1 along the length of each cell-cell contact, but does not extend beyond the boundary of these contacts. As the monolayer becomes polarized, the distribution of Sec6/8 becomes restricted to the apex of the lateral membrane and no longer extends along the length of each cell-cell contact. Although this distribution is distinct from that of E-cadherin in polarized cells, localization of the Sec6/8 complex at the apical junctional complex is still dependent on calcium-dependent cell-cell adhesion. Treatment of cells with EGTA disrupts E-cadherin-mediated cell-cell contacts and results in dissociation of Sec6/8 from the plasma membrane. After readdition of calcium to the culture medium, the Sec6/8 complex is rerecruited to the plasma membrane and relocalizes to the apical junctional complex with kinetics similar to those observed for ZO-1.

In steptolysin O (SLO)-permeabilized MDCK cells, antibodies to Sec8 significantly reduced delivery of low-density lipoprotein (LDL) receptor-containing vesicles to the basolateral membrane, whereas targeted delivery of p75^NTR to the apical plasma membrane was unaffected (118). We speculate that antibodies bound to the Sec6/8 complex inhibit delivery of LDL receptor-containing vesicles by sterically hindering vesicle docking. Because the Sec6/8 complex is restricted to the apex of the lateral membrane, this result implies that vesicle docking and fusion occur near the apical junctional complex. This observation is consistent with previously reported localization of multiple rab proteins at this site (see above; Refs. 155, 374, 391). Furthermore, the observed redistribution of rab3B and rab13 into cytosolic vesicular structures after extracellular calcium depletion (374, 391) could reflect the accumulation of transport vesicles that are unable to dock efficiently with the plasma membrane in the absence of the Sec6/8 complex. If the Sec6/8 complex specifies a subdomain of the plasma membrane for efficient vesicle docking, we anticipate that basolateral proteins would be delivered less efficiently to the plasma membrane in contact-naive MDCK cells because the Sec6/8 complex is not membrane bound. Similarly, when the Sec6/8 complex is recruited to the plasma membrane to sites of cell-cell contact, we would anticipate an increased efficiency of delivery of basolateral proteins. These predictions are supported by previously published results. Detailed studies of the trafficking of newly synthesized desmoglein I, a basolateral membrane protein, showed than <10% was transported to the plasma membrane of contact-naive MDCK cells during a 1-h chase (278). However, upon initiation of cell-cell contacts, desmoglein I was rapidly (half-life ~30 min) and efficiently (>90%) delivered to the plasma membrane (278).

Mechanisms regulating assembly of targeting patches for transport vesicles on different membrane domains are unknown. Detailed studies of the kinetics and fidelity of membrane protein trafficking between the TGN and the basolateral membrane indicate that direct delivery occurs within 6 h of induction of cell-cell adhesion (117, 224). That this process is so rapid indicates that cellular components involved in sorting and targeting of membrane proteins to the basolateral membrane domain are present in nonpolarized cells before cell-cell adhesion. Furthermore, because direct targeting requires cadherin-mediated cell-cell adhesion, it is likely that components of the targeting patch, at least for vesicles containing basolateral proteins, are somehow associated with the cadherin adhesion complex. Specialized cytoskeletal networks assembled at different membrane domains in response to spatial cues may organize vesicle targeting patches. In turn, these targeting patches specify protein delivery from sorting compartments, thereby reinforcing and maintaining differences in cell surface protein distributions that were initiated by the spatial cue(s).

If cell-cell adhesion promotes the localized assembly of a basolateral-specific vesicle targeting patch on the contacting membrane, how does the apical membrane form? Developing epithelial tissues in vivo arise from cell aggregates, which lack a free membrane domain (298, 373). Recruitment of the Sec6/8 complex to sites of cell-cell adhesion likely establishes a targeting patch for basolateral transport vesicles, but several lines of evidence indicate that apical transport vesicles fuse very poorly with these contacting plasma membranes. First, contact between a cell and the ECM is sufficient to restrict apical membrane proteins to the free, noncontacting surface (299, 371). Second, epithelial cell aggregates grown in suspension culture restrict apical membrane proteins to the free surface (371). Transfer of these aggregates into a collagen gel deprives the cells of their free surface, and apical membrane proteins are rapidly removed from the surface and degraded (372). Finally, treatment of epithelial cells with nocodazole significantly reduces the efficiency of vesicle transport to the apical plasma membrane (362). However, apical vesicles do not fuse with the basolateral membrane, but rather accumulate intracellularly and may in time fuse with each other to form large vacuole-like structures (110). Therefore, for apical transport vesicles to fuse with the plasma membrane, a cell contacted on all sides by other cells and the ECM must first establish a noncontacting membrane. The SNARE hypothesis may also account for the de novo formation of such a membrane domain.

We propose the following scenario for how an apical surface forms de novo. Trans-Golgi network-derived transport vesicles containing previously sorted apical protein cargo would fuse very inefficiently with the plasma membrane along cell-cell contacts. If all surfaces of the cell were in contact with other cells or with the ECM, then TGN-derived apical transport vesicles would accumulate in the cytoplasm. Under such conditions, these vesicles may tend to fuse with one another by homotypic vesicle fusion. Homotypic vesicle fusion has been most thoroughly described for yeast vacuoles, where it is clear that both v- and t-SNARE proteins are associated in a complex on both "donor" and "target" membranes (121, 221, 256, 355). This protein complex is dissociated by the action of NSF and -SNAP before docking, which serves to activate the SNARE proteins for subsequent membrane fusion. Because v- and t-SNAREs have been described together on a number of types of vesicles, it is conceivable that post-Golgi apical transport vesicles contain both v- and t-SNAREs (25, 48, 99, 100, 282, 370). Under appropriate conditions, these could mediate homotypic fusion between apical transport vesicles, leading to the generation of a large intracellular luminal compartment. Such compartments have been described (110, 364, 373). Delivery of this luminal compartment to the plasma membrane may be mediated by the low levels of apical t-SNAREs present on the basolateral plasma membrane. Insertion of apical luminal compartments into the lateral membrane has been visualized (110, 265, 365). Once inserted in the plasma membrane, the preformed apical membrane may be prevented from mixing with the basolateral membrane domain by the rapid movement and assembly of tight junction components to a site between the two membrane domains (see sect. IVC).

Localized assembly of cytoskeletal and signaling complexes at sites of cell adhesion has implications for local and global changes in cellular organization. Locally, formation of an actin cytoskeleton precedes the assembly of a fodrin-based membrane skeleton at sites of cell adhesion (254). Fodrin is a long, rod-shaped protein that assembles into a protein skeleton with a complex of actin, protein 4.1, adducin, and other proteins (reviewed in Ref. 22). The fodrin membrane skeleton is associated with the cadherin/catenin complex (253), and although the associations are not well defined, the linkage could be mediated through binding of either actin or fodrin to -catenin (202). Fodrin also binds to ankyrin, which in turn binds with high affinity to integral membrane proteins, including Na⁺-K⁺-ATPase (255) and Cl/HCO₃ exchanger (reviewed in Ref. 22). These interactions result in localized assembly of the fodrin-based membrane skeleton and restriction of specific membrane proteins to sites of cell adhesion.

Assembly of the fodrin-based membrane skeleton may play a direct role in the early formation of a basolateral membrane domain at sites of cell-cell contact by directing the retention and accumulation of specific proteins that have affinity for the fodrin lattice. Several lines of evidence highlight the importance of interactions between cadherin/catenin complexes and the membrane skeleton in localization of certain proteins, such as Na⁺-K⁺-ATPase, to sites of cell-cell adhesion. Ectopic expression of E-cadherin in nonpolarized fibroblasts (229) or polarized retinal pigmented epithelial cells (213) induces the assembly of a membrane skeleton at cell-cell contact sites and leads to a restricted localization of Na⁺-K⁺-ATPase to these sites. However, when a truncated E-cadherin form lacking the catenin binding domain was expressed, neither fodrin nor Na⁺-K⁺-ATPase was localized to cell-cell contacts (229). Significantly, overexpression of the actin-binding domain of fodrin appears to competitively inhibit the association of actin with the membrane and results in both the disruption of membrane skeleton organization and the relocalization of Na⁺-K⁺-ATPase into cytoplasmic vesicles (153). The concept of the membrane skeleton as a protein sorting machine is conceptually attractive, since it predicts that certain proteins, such as Na⁺-K⁺-ATPase, would be preferentially excluded from endocytic pathways and accumulate at cell-cell contact sites (19). In contrast, mistargeted membrane proteins would not be incorporated into the membrane skeleton and consequently be internalized more rapidly. Data to support these predictions have been presented (122, 252). Thus assembly of a membrane skeleton may be one of the first steps in propagating signals from extrinsic spatial cues to initiate both localized assembly of a specialized membrane domain at sites of cell adhesion and global changes in the organization of other cytoskeletal complexes and membrane compartments (see sect. V).

The organization of membrane-associated actin cytoskeleton on the apical membrane has been well characterized (236). A central core of bundled actin filaments inserts into each microvillus that protrudes from the apical surface. This actin filament organization is regulated by the actin-associated proteins fimbrin and villin (34, 36, 37). Each actin bundle inserts into a fodrin-actin meshwork underlying the apical membrane (terminal web) (143-145, 281). Although the specialization of the actin cytoskeleton at the apical membrane is important for increasing cell surface area, less is known about linkage of membrane proteins to this membrane skeleton, or whether it functions to maintain polarized protein distributions.

The tight junction (zonula occludens), the most apical structure of the junctional complex, acts as a selective permeability barrier to the paracellular space (gate function; Ref. 75) and an intramembranous fence to prevent free mixing of membrane domain-specific proteins and lipids (fence function; Refs. 76, 360, 361).

The tight junction has a well described but poorly understood structure. Freeze-fracture electron microscopy has depicted the tight junction as a continuous network of parallel and interconnected strands that circumscribe the apex of lateral membranes of adjacent cells (57). Early studies sought to establish a relationship between tight junction strand number and function (57), but it has been difficult to extrapolate generalizations to all cell types (335). Little is known about how tight junction functions are regulated in different physiological or pathological conditions, nor the molecular basis for differences in the paracellular permeability of "leaky" (e.g., proximal renal tubule) and "tight" epithelia (e.g., distal renal tubule).

The protein composition and organization of tight junction are being uncovered. Occludin is the only tight junction transmembrane protein identified so far (96). However, its function in regulating tight junction structure is uncertain (310). Immunoelectron microscopy combined with freeze fracture has shown that occludin is localized to tight junction strands (93). Overexpression of full-length occludin or mutant occludin lacking the cytoplasmic domain (15, 226) or addition of a synthetic peptide corresponding to the second extracellular loop of occludin (384) perturbs tight junction gate function. How occludin might seal the extracellular space remains unknown, although hydrophobic interactions through the glycine-rich extracellular domains of occludin may be important (384). Significantly, ectopic expression of occludin in fibroblasts confers cell-cell adhesion, indicating that occludin also has an adhesive function (359).

Several cytoplasmic proteins interact either directly or indirectly with occludin, including ZO-1, ZO-2, and ZO-3 (97, 126, 167, 169, 380). These proteins may act as a protein scaffold to organize occludin at the tight junction. For example, the spatial organization of occludin on the membrane of fibroblasts requires coexpression of ZO-1 (359). ZO-1, ZO-2, and ZO-3 also contain PDZ domains and SH₃ domains (81, 126, 167, 169, 380) and may recruit signaling molecules and the actin cytoskeleton to the tight junction.

A number of signaling molecules have been implicated in the regulation of tight junction function, including tyrosine kinases, cAMP, Ca²⁺, protein kinase C, heterotrimeric G proteins, and phospholipase C (7, 50). One target common to these molecules is actin (7) and the perijunctional actin-myosin ring located subjacent to the apical junction complex (205). It has been proposed that contraction of perijunctional actin filaments and the resulting centrifugal traction on tight junction membrane regulate tight junction permeability (205).

	V. TRANSLATION OF LOCALIZED SPATIAL INFORMATION INTO GLOBAL CHANGES IN CELL MORPHOLOGY

Top Previous Next References

Globally, the generation of physical and molecular asymmetry at the cell surface by cell adhesion leads to formation of the apical membrane in the noncontacting (free) cell surface and the basolateral membrane along the contacting cell surface. Although our understanding of how the basolateral membrane forms is increasing, much less is known about how formation of the apical membrane is induced. Because the apical membrane is not in contact with other cells or the ECM, it is likely that the mechanisms involved in apical membrane formation are different from those that establish the basolateral membrane domain. We propose that the apical membrane may arise from exocytosis of a preformed intracellular luminal compartment (see sect. IVA). It is possible that spatial information from adhesive contacts on the basal (lateral) membrane is somehow transduced through the cytoskeleton to the free cell surface. Underlying these cell surface changes is a reorganization of cytoskeletal structures (Fig. 2). The importance of the cytoskeleton in eukaryotic cells is demonstrated by its involvement in cellular events ranging from, but not limited to, mitosis, cytokinesis, cell motility, maintenance of cell shape, organelle and protein distribution, secretion, and endocytosis (35, 39, 42, 59, 178, 223, 337).

View larger version (34K): [in this window] [in a new window]   FIG. 2.   Global changes in cytoskeletal organization during establishment of a polarized monolayer. In absence of cell-cell contacts, cytoskeleton and secretory compartments in an epithelial cell are organized similar to that in a fibroblast. Microtubule network originates from a broad perinuclear region, concomitant with localization of Golgi complex, and extends outward to cell periphery. Actin cytoskeleton (microfilaments) is primarily organized into focal contacts that arise from sites of cell-substrate interactions. After initiation of cell-cell contacts, microtubules reorganize to form a dense mat of short, randomly oriented microtubules in subapical membrane cytoplasm and along basal membrane. Long cortical bundles of microtubules form parallel to lateral membrane along that apical-basal axis of cell. Coincident with microtubule reorganization, Golgi complex becomes localized to apical cytoplasm. At apical membrane, actin microfilaments form core of long membrane protrusions, termed microvilli, that are characteristic of apical membrane of absorptive epithelia. Actin cytoskeleton is also distributed in a ring around apex of lateral membrane at zonula adherens just beneath zonula occludens. Along basolateral membrane, microfilaments are associated with membrane cytoskeleton (M-CYTO) and focal adhesion sites. This distribution is linked to localized assembly of cytoskeletal structures and signaling complexes at sites of cell-cell and cell-substrate contacts as discussed in text.

Morphogenesis of the apical membrane involves assembly of a unique, actin-based cytoskeletal structure that forms the core of long membrane protrusions, termed microvilli, that are characteristic of the apical membrane of absorptive epithelia (236). As described above, the microvillus core comprises a bundle of actin filaments that are cross-linked by villin (37) and fimbrin (34, 36) and linked laterally to the membrane by myosin I (49, 61). These actin bundles extend to the base of each microvillus and are linked together by myosin I and a fodrin lattice called the terminal web (143-145, 281). Ectopic expression of villin in fibroblasts by transient transfection (92) or microinjection (89) causes a redistribution of actin from stress fibers into new structures resembling apical microvilli that also contain fimbrin and ezrin. This effect was shown to require the actin bundling activity of villin (89, 92). Furthermore, expression of villin anti-sense RNA in polarized Caco-2 intestinal epithelial cells causes a reversible loss of apical microvilli (62). The precise role of villin in morphogenesis of apical microvilli is uncertain, however, because mice lacking villin have intact microvilli (287). Therefore, it is likely that in the absence of one key component of the microvillus core, other proteins with overlapping or redundant functions can fill in.

It is unknown how proteins that comprise the microvillus core become localized to the forming apical membrane. Before the appearance of microvilli in developing epithelia, villin is found in the apical cortex and near the adherens junction at sites of cell-cell contact (80, 135). Because the adherens junction contains a high concentration of cadherin/catenin complexes and actin filaments, villin may become localized to the apical cortex through its association with these cytoskeletal complexes. In addition, assembly of the terminal web may be linked to formation of the membrane skeleton on the lateral membrane, since both structures share fodrin as a common component (143, 254, 297). Similarly, the cortical actin that surrounds single cells attached to ECM could act to nucleate the assembly of actin structures on the free cell surface. As well as forming the core of individual microvilli in polarized epithelial cells, the actin cytoskeleton is distributed in a ring around the apex of the lateral membrane at the site of the adherens cell-cell adhesion junction, and along the lateral and basal membranes (223, 251). This distribution is linked to localized assembly of cytoskeletal structures and signaling complexes at sites on cell-cell contacts as discussed above.

After the establishment of cell-cell and cell-substratum contacts, microtubules become reorganized in the apical and basolateral cytoplasm. In nonpolarized MDCK cells, microtubules originate from a broad perinuclear region of the cytoplasm and extend outward to the plasma membrane in a uniform polarized array (plus ends of microtubules at the cell periphery). After the initiation of cell-cell and cell-substratum contacts, the microtubules reorganize to form a dense mat of short, randomly oriented microtubules in the subapical membrane cytoplasm and a randomly organized mat of short microtubules along the basal membrane. Long cortical bundles of microtubules with the same polarity (minus ends of microtubules oriented toward the apical surface of the cell) form parallel to the lateral membrane along that apicobasal axis of the cell (13, 117). Thus microtubules apparently reorganize around subapical sites during the establishment of polarity. Microtubule reorganization may be linked to the transition from a flat fibroblast-like morphology to the columnar cell shape characteristic of a polarized epithelial cell. Mechanisms that regulate microtubule reorganization after cell adhesion are not known. It is possible that the orientation of microtubule assembly in the apicobasal axis is determined by linkage of microtubules to cytoskeletal complexes on lateral and basal membranes, or to the actin cytoskeleton forming under the apical membrane domain.

Coincident with microtubule reorganization, compartments of the secretory apparatus that are involved in protein sorting become localized to the apical (Golgi, TGN, and apical endosome) and basal (basolateral endosome) cytoplasm. Microtubule organization is required to maintain these distributions, but again, the mechanisms involved are not well understood. Microtubule motor proteins, such as dynein or kinesin, may translocate these compartments toward the minus or plus ends of polarized microtubules, resulting in their distribution in the apical and basal cytoplasm, respectively (reviewed in Ref. 24). In addition to its spatial distribution, the three-dimensional structure of the Golgi apparatus appears to be dependent on microtubules (184). Treatment of cells with microtubule-depolymerizing drugs results in fragmentation and redistribution of the Golgi apparatus throughout the cytoplasm (280, 347, 353). These Golgi membrane fragments do not appear to be randomly distributed but rather are organized around peripheral sites that correspond to endoplasmic reticulum exit sites (59). Trafficking of proteins through the Golgi apparatus is inhibited immediately after microtubule disruption but is subsequently restored after the reorganization of Golgi fragments at peripheral sites adjacent to the endoplasmic reticulum (59).

	VI. SORTING AND TRANSPORT OF PROTEINS TO APICAL AND BASOLATERAL MEMBRANE DOMAINS REINFORCES AND MAINTAINS CELL SURFACE ASYMMETRY ESTABLISHED BY EXTRACELLULAR CONTACTS

Top Previous Next References

To compensate for protein turnover at the cell surface, and to maintain polarized distributions of cell surface constituents, newly synthesized proteins are sorted in the Golgi complex and endosomes and delivered to either the apical or basolateral membrane. Targeted delivery of proteins to different membrane domains involves three distinct processes: protein sorting into separate transport vesicles in the sorting compartment, targeting of vesicles to specific membrane domains, and docking and fusion of vesicles with the correct membrane domain. The fidelity and efficiency of vesicle targeting is facilitated by the organization of the secretory apparatus and microtubules (see sect. VII). Docking and fusion of transport vesicles with the correct plasma membrane domain is ensured by domain-specific vesicle targeting patches that we propose are established in response to cell adhesion (see sect. IVA).

Sorting of apical and basolateral membrane proteins occurs in the TGN and endosomes (161, 218, 301). Basolateral sorting in each of these compartments is dependent on identical cytoplasmic amino acid sequences, indicating that the sorting machinery is likely similar in the two organelles (11, 219). However, recent studies indicate that this may be an oversimplification (261). Basolateral sorting signals frequently contain a critical tyrosine residue within the amino acid sequence NPXY or YXXO/ (where X is any amino acid and O/ is an amino acid with a bulky hydrophobic group) (350). In several cases, these motifs are predicted to form a structure known as a "tight -turn" (60, 77). Tyrosine-based motifs mediate basolateral sorting of several proteins [e.g., receptors for LDL (159, 217) and asialoglycoproteins (108), lysosomal acid phosphatase (289), lysosomal membrane glycoprotein LAMP-1 (147), envelope glycoproteins of VSV G (345, 346) and human immunodeficiency virus (201), and mutated forms of p75^NTR (191, 235) and HA (38)]. In some cases, a dihydrophobic motif serves to target the protein basolaterally [e.g., Fc receptor (158, 220) and myosin heavy chain class II invariant chain (262, 328)]. Finally, a growing number of basolateral sorting signals bear little or no sequence similarity to these motifs [e.g., pIgR (10), neural cell adhesion molecule (193), transferrin receptor (261)]. Some of these latter signals have been suggested to form a peptide structure that comprises a tight -turn and therefore may resemble the tyrosine-based signals (10, 193). However, it is unknown whether these structures are present in the context of the native protein.

Basolateral sorting signals superficially resemble signals responsible for endocytosis and protein sorting to diverse cellular locations, including early and late endosomes, lysosomes, TGN, and specialized organelles such as phagosomes and the antigen-processing compartment in B lymphocytes (reviewed in Ref. 211). Although YXXO/-based signals mediate sorting to many organelles, the specificity of these signals is restricted by other factors, including surrounding amino acid sequences (125, 147, 220, 284), proximity of the targeting signal to the transmembrane domain (303), and phosphorylation (27, 192, 212, 263). Furthermore, the oligomeric state of the transported protein can alter the sorting activity of dihydrophobic signals (9).

Both YXXO/- and dihydrophobic-based sorting signals selectively bind clathrin adaptor protein complexes AP-1 and AP-2 (27, 146, 263, 264, 296). Very solid evidence exists for the interaction between tyrosine-based signals and the medium (µ) chains of these complexes (27, 263, 264). Although both tyrosine- and dihydrophobic-based signals can bind AP-1 and AP-2 complexes in vitro, proteins with one type of signal do not cross-compete with proteins carrying the other type of signal, implying that distinct mechanisms mediate sorting of each class of signals (212). In support of this conclusion, recent evidence indicates that dihydrophobic signals bind to the -chains rather than the µ-chains of adaptor complexes (291). Although interactions between tyrosine- and dihydrophobic-based signals and AP-1/AP-2 complexes are responsible for cargo-selective sorting into TGN- and plasma membrane-derived clathrin-coated vesicles, the mechanisms responsible for basolateral sorting remain unknown. Certain basolateral proteins are delivered to early endosomes before arrival at the plasma membrane (98, 194). However, one protein that follows this route to the plasma membrane, transferrin receptor, does not bind the µ₁-chain of TGN AP-1 complexes (263), indicating that AP-1/clathrin-coated vesicles do not mediate basolateral transport of transferrin receptors. A recently described adaptor complex, AP-3 (73, 74, 329, 330), also interacts with tyrosine- and dihydrophobic-based signals (73, 148, 329). Initial studies suggested that AP-3 is a component of nonclathrin coats (329, 330), but recent work has demonstrated an association between the ₃-appendage domain of AP-3 and clathrin (72). Thus AP-3 appears to be involved in the formation of a novel class of clathrin-coated vesicles in the TGN and endosomes (72, 336). The AP-3 complex is required for protein sorting to the yeast vacuole (63) and pigment granule formation in Drosophila (270), but a function in basolateral protein sorting has not yet been shown.

Protein sorting to the apical plasma membrane is dependent on motifs present in the luminal domain or membrane anchor, rather than the cytoplasmic domain (reviewed in Ref. 176). Certain membrane proteins are anchored to the lipid bilayer by a glycosylphosphoinositol (GPI) group. Strong evidence supports a role for this structure in apical sorting in MDCK cells (40, 199, 382), although this signal does not function as an apical sorting determinant in all epithelial cells (393). The identity of signals responsible for apical sorting of membrane-spanning proteins is much less clear. Whereas all basolateral sorting signals characterized to date are short cytoplasmic peptides, apical sorting signals appear to be located in the large, highly folded extracellular domain. This conclusion is based on findings that viral protein chimeras (231, 305), "tail-minus" mutants of basolateral membrane proteins (159, 239, 289), and soluble extracellular domains of apical and basolateral membrane proteins (40, 193, 199, 238, 288, 368, 378, 389) are all targeted to the apical membrane of polarized MDCK epithelial cells. Peptide-based apical sorting signals have not been identified in any of these proteins.

Early studies examined a potential role of N-glycans in apical sorting (116, 304). Correlative evidence for an involvement of these structures has been reviewed elsewhere (85). Experimental evidence for the involvement of N-glycans in apical sorting of certain proteins has been presented (120, 181, 316, 356), but apical sorting of many proteins occurs independently of N-glycosylation (112, 156, 214, 290, 354, 389). For at least one protein, the neurotrophin receptor p75^NTR, apical sorting information has been localized to an O-glycosylated "stalk" that is adjacent to the transmembrane domain (389). When this signal is removed, p75^NTR is very efficiently (>95%) targeted to the basolateral membrane domain. The mechanisms of carbohydrate-mediated apical sorting are not known. One potential mechanism involves recognition of carbohydrate moieties by sorting lectins, such as VIP36 (84, 86), which is hypothesized to partition into microdomains of the TGN along with other apical membrane proteins and lipids (see below).

Regardless of the nature of the sorting signal, the mechanism of protein sorting in the TGN and endosomes likely employs a simple and common theme. Sorting mechanisms are poorly understood, but the basic principle may involve segregation of different proteins by localized clustering in the plane of the lipid bilayer. Apical sorting has been proposed to involve formation of glycolipid- and cholesterol-containing membrane domains, or "rafts," in the exoplasmic leaflet of the Golgi (301, 326). The biochemical properties of these rafts have been reviewed recently (325). Some apical membrane proteins are clustered into glycosphingolipid rafts during transport through the Golgi. Clustering may be mediated by transmembrane domains [e.g., influenza virus HA (317) and neuraminidase (185)] or GPI anchors (41, 107, 394). After insertion into the apical plasma membrane, GPI-anchored proteins are initially clustered but gradually disperse in the plane of the bilayer (124), whereas HA apparently remains clustered (317). The formation of rafts can be disrupted by inhibiting sphingolipid synthesis with fumonisin B₁ (225) or by depleting cells of cholesterol after treatment with methyl--cyclodextrin (317). These treatments inhibit apical sorting of GPI-anchored proteins but have different effects on the secretory protein gp80/clusterin (177, 225). Furthermore, disruption of raft formation by cholesterol depletion causes missorting of influenza virus HA (177), but apical transport of many other proteins occurs independently of rafts (12, 64, 383). Therefore, apical sorting likely involves more than one mechanism, but the details of these mechanisms are obscure.

Certain basolateral membrane proteins (e.g., Na⁺-K⁺-ATPase) may be sorted by exclusion from glycosphingolipid rafts (225). For this type of protein, efficient basolateral sorting may be achieved in the absence of an active basolateral sorting signal. We propose that sorting of many proteins for which basolateral sorting signals have been actively sought, but not identified, may occur by this mechanism (385, 388). Other basolateral proteins may be clustered into microdomains in the TGN by a cytosolic protein coat structure that assembles onto the membrane by recognizing a sorting signal in the cytoplasmic domain of proteins (134, 180, 244, 319). However, as mentioned above, proteins that interact with basolateral sorting signals have not yet been identified.

After apical and basolateral membrane proteins are sorted into distinct subdomains of the TGN, cargo must be packaged into transport vesicles. High-voltage electron microscopic studies have revealed that the TGN is composed of multiple distinct membrane tubules that possess either clathrin coats or a novel "lacelike" coat (188). Each tubule produces only one type of vesicle, which suggests that protein sorting and vesicle budding are distinct processes (188). However, vesicle budding mechanisms are not understood. One protein implicated in the budding of basolateral transport vesicles is p200 (reviewed in Ref. 243). Purification and sequencing have shown p200 to be identical to the heavy chain of nonmuscle myosin II (163, 242). P200/myosin II is recruited onto Golgi membranes upon activation of heterotrimeric G proteins (66, 163, 242) and is released from membranes by treatment with brefeldin A (249). P200/myosin II is present on non-clathrin-coated vesicles that are distinct from coatamer-coated vesicles (250). In MDCK cells, p200 is present on basolateral transport vesicles that contain VSV G and absent from apical transport vesicles containing influenza HA (242). Immunodepletion of p200 from semi-intact MDCK cells blocks vesicular release of VSV G, but not influenza HA (242). Vesicle budding is restored by readdition of myosin II to the system. However, p200 depletion had no affect on basolateral transport in SLO-permeabilized MDCK cells, although technical differences between this study and the vesicle budding experiment may explain different results (164). Experiments involving the p200 monoclonal antibody must be interpreted with caution, since the antibody appears to cross-react with other proteins (e.g., filamin and -COP; see Refs. 164, 324). Nonetheless, depletion of myosin II by sedimentation with phalloidin-polymerized actin fibers, and several independent lines of evidence (e.g., inhibition of myosin II ATPase activity and competition of actin-myosin interaction) also reduced basolateral vesicle budding (242). Therefore, p200/myosin II appears to be involved in the budding of basolateral, but not apical transport vesicles from the TGN.

Vesicle budding from the Golgi in vitro is dependent on an 85-kDa cytosolic complex composed of p62 and a small GTPase (172). This protein complex cycles on and off Golgi membranes in a phosphorylation-dependent manner. Purification and sequencing of p62 has revealed homology with the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) (173). Upon recruitment to the membrane, p62 is thought to assemble with the 100-kDa catalytic subunit of PI 3-kinase to facilitate vesicle budding (173). The mechanism is not clear, but changes in lipid charge may promote membrane curvature required to form a vesicle (321).

Fission of transport vesicles likely requires the activity of a Golgi-associated dynamin (174). The function of dynamin has been most thoroughly characterized in endocytosis, where it has been shown to form rings at the neck of invaginated clathrin-coated pits (339). It has been proposed that a conformational change in the dynamin ring, driven by GTP hydrolysis, is involved in vesicle fission (69). An isoform of dynamin, likely dynamin 2, colocalizes with TGN38 on Golgi membranes (174). Antibody inhibition studies as well as immunodepletion/add-back experiments have provided strong evidence in support of a role for dynamin in budding of both clathrin-coated and non-clathrin-coated vesicles in vitro (174).

Production of apical transport vesicles has been suggested to involve VIP21/caveolin (277). Evidence in support of this hypothesis is indirect. Caveolin was simultaneously identified as a component of plasma membrane caveolae (306) and TGN-derived exocytic vesicles (186). The properties of glycosphingolipid/cholesterol rafts implicated in apical sorting are similar to those of isolated plasma membrane caveolae (88, 222). VIP21/caveolin is a cholesterol-binding protein (241) that is enriched in these rafts (313, 394). Madin-Darby canine kidney cells express two caveolin isoforms (caveolin-1 and caveolin-2) (318). Both proteins are present on post-Golgi transport vesicles, but apical vesicles contain primarily caveolin-1, whereas basolateral vesicles contain roughly equal amounts of the two isoforms (318). Anti-caveolin-1 antibodies significantly reduced delivery of influenza HA to the apical membrane in SLO-permeabilized MDCK cells, whereas basolateral transport of VSV G protein was unaffected (318). However, it is unlikely that caveolin alone is responsible for apical sorting. Fischer rat thyroid cells, which sort GPI-anchored proteins basolaterally (393), do not express caveolin-1 (394) and do not form plasma membrane caveolae (197). Expression of caveolin-1 in these cells results in production of caveolae, but not in apical sorting of GPI-linked proteins (197).

	VII. ROLE OF THE CYTOSKELETON IN VESICLE TRANSPORT

Top Previous Next References

The cytoskeleton has been the focus of studies to identify mechanisms involved in vesicle trafficking to specific membrane domains. The exact role of actin in vesicle trafficking is unknown. However, vesicle fusion with the plasma membrane may be preceded by the localized depolymerization of actin at the membrane (131, 132, 223). Thus actin may act as a fence to prevent access of vesicles with the plasma membrane before membrane docking. In addition, disruption of the actin cytoskeleton appears to inhibit apical endocytosis and transcytosis, whereas basolateral endocytosis and vesicle trafficking between the TGN and apical or basolateral membrane domain remain unaffected (113, 210, 248, 267, 275, 311). Furthermore, the presence of myosin I on purified, post-TGN transport vesicles indicates that the actin cytoskeleton is involved in vesicle trafficking (82).

Although microtubules have been shown to be involved in basolateral to apical transcytosis and apical recycling, their role in TGN to plasma membrane delivery is somewhat controversial (32, 160, 216). It has been suggested that microtubule reorganization and the coincident relocalization of the Golgi complex to apical region of the cell is specialized for efficient delivery of proteins from the TGN to the apical membrane (362). Previous studies have shown that vesicle transport between the TGN and apical membrane is slowed after disruption of microtubules with colchicine or nocodazole, whereas transport to the basolateral plasma membrane remains relatively unaffected (2, 78, 109, 216, 295, 362). Nevertheless, basolateral transport vesicles bind to microtubules in vitro (358), and delivery of VSV G protein to the basolateral membrane appears to require microtubule motor proteins (189).

Direct examination of the role of microtubules in establishing direct delivery pathways during development of epithelial polarity demonstrates that a microtubule/Golgi organization characteristic of polarized epithelial cells does not represent a specialized structural framework in epithelial cells for vesicle targeting from the TGN to either the apical or basolateral membrane (117). Efficient and specific direct delivery pathways for vesicles between the TGN and apical or basolateral plasma membrane were shown to be established rapidly after the induction cell-cell and cell-substratum contacts. This occurred before the global reorganization of the microtubule/Golgi complex characteristic of polarized epithelial cells. Thus microtubules appear to facilitate but not specify the delivery of vesicles to either the apical or basolateral plasma membrane in MDCK cells with a microtubule/Golgi distribution characteristic of either nonpolarized or polarized epithelial cells. This would indicate that either the polarity of microtubules between the TGN and different membrane domains is not important with respect to targeting of proteins, or vesicles carrying these proteins can adapt to different microtubule orientations due to the presence on their membrane of both plus end- and minus end-directed microtubule motors. It is important to note, however, that although the secretory protein gp80/clusterin was targeted to the apical plasma membrane domain regardless of the specific microtubule/Golgi organization, appropriate delivery was dependent on intact microtubules (117, 275). Similar results have been reported for the targeting of basement membrane proteins in MDCK cells and LLC-PK₁ renal epithelial cells and serum albumin in rat hepatocytes after microtubule disruption (28, 67, 314). Mistargeting of secretory proteins after microtubule disruption indicates that secretory proteins are sorted into a population of vesicles that have promiscuous docking capabilities with both membrane domains. Alternatively, the fragmentation and dispersal of the Golgi apparatus after microtubule disruption may reduce the efficiency with which secretory proteins are sorted into the appropriate population of transport vesicles, ultimately resulting in their mistargeting. Regardless, secretory proteins are sorted into a class of vesicles with distinct transport characteristics as compared with vesicles containing plasma membrane proteins (28, 67, 117, 314).

If the reorganization of microtubules and the Golgi complex in polarized epithelia is not required to specify vesicle delivery from the TGN to apical and basolateral membranes, what function might this reorganization serve? Although both fibroblasts and epithelial cells target proteins from the TGN to the plasma membrane, polarized epithelial cells have the unique ability to transport proteins between distinct plasma membrane domains, a process termed transcytosis (17, 149, 190, 215, 240). Epithelial cells use transcytosis both to establish the polarized distribution of plasma membrane proteins and as a mechanism for selective transport of membrane receptors and macromolecules between apical and basolateral plasma membrane domains (17, 237, 298). Protein targeting studies conducted in hepatocytes, Caco-2 cells, and MDCK cells have demonstrated that the degree to which transcytosis is used to establish polarized distributions of proteins depends on the cell type (237). Nevertheless, the hepatocyte-derived cell line WIF-B, Caco-2 cells, and MDCK cells possess similar microtubule distributions. In polarized cultures of all three cell types, microtubules are nucleated in the apical region of the cells (232). Furthermore, treatment of MDCK cells, Caco-2 cells, and hepatocytes with microtubule-disrupting agents inhibits basolateral to apical transport of polymeric immunoglobulin receptor, dipeptidylpeptidase IV and aminopeptidase N, and bile acids (29, 32, 160, 216, 314). Results from our laboratory indicate that a microtubule/Golgi organization characteristic of either a nonpolarized or polarized epithelial cell is sufficient to facilitate delivery of plasma membrane proteins between the TGN and either the apical or basolateral plasma membrane domain of epithelial cells (117). However, transition from a nonpolarized to polarized organization may be required for basolateral to apical transcytosis, a process tailored to functions of polarized epithelial cells.

	VIII. A HIERARCHY OF STAGES FOR ESTABLISHING CELL POLARITY

Top Previous Next References

In summary, we propose that epithelial cell polarity is initiated by the establishment of structural and molecular asymmetry at the cell surface by extrinsic spatial cues involving cell-cell and cell-ECM adhesion (Fig. 3). Extrinsic cues require specific membrane receptors that mark the site of the cue on the cell surface. Marking the site of the spatial cue restricts subsequent signaling to the immediate vicinity of the cue, thereby defining molecular and structural asymmetry in the membrane between the site of the spatial cue and the rest of the cell surface. The spatial cue induces localized assembly of an actin cytoskeleton matrix, leading to global changes in cell organization. Spatial information from the cue is reinforced by localized assembly of the cytoskeleton and a targeting patch for transport vesicles and is propagated along the membrane, and into the cell interior, by changes in the distribution and organization of actin and microtubules. Concomitant with microtubule reorganization, sorting compartments of the secretory apparatus reorient in the cytoplasm along an axis of polarity relative to position of the cue(s). Plasma membrane proteins, sorted into distinct transport vesicles by virtue of sorting signals in the TGN, are delivered to targeting patches assembled at specific membrane domains. This process reinforces and stabilizes the molecular and structural asymmetry of the cell surface that was started by the spatial cue.

View larger version (35K): [in this window] [in a new window]   FIG. 3.   A hierarchy of stages for establishing cell polarity. Extrinsic spatial cues involving cell-cell and cell-ECM contacts are marked and interpreted by adhesion receptors and associated signaling complexes. Marking of site of spatial cue restricts subsequent signaling to immediate vicinity of cue. These interactions define a molecular and structural asymmetry in membrane between site of spatial cue and rest of cell surface. Spatial information from cue is reinforced by localized assembly of cytoskeleton and a targeting patch for transport vesicles. Spatial information from cue is propagated along plasma membrane (PM), and into cell interior, by changes in distribution and organization of actin and microtubules. Concomitant with microtubule reorganization, sorting compartments of secretory apparatus reorient in cytoplasm along an axis of polarity relative to position of cue(s). Plasma membrane proteins, sorted into distinct transport vesicles in trans-Golgi network, are delivered to targeting patches assembled at specific membrane domains. This process reinforces and stabilizes molecular and structural asymmetry of cell surface that was initiated by spatial cue.

	FOOTNOTES

   This work was supported by National Institute of General Medical Sciences Grant GM-35527 (to W. J. Nelson) and a Digestive Disease Center Pilot/Feasibility Study Grant (to K. K. Grindstaff). K. K. Grindstaff is the recipient of National Institute of Diabetes and Digestive and Kidney Diseases Postdoctoral Fellowship DK-09368. C. Yeaman was supported by Cancer Biology Grant CA09302 awarded to Stanford University from the National Cancer Institute and a Walter V. and Idun Y. Berry Fellowship.

	REFERENCES

Top Previous

1.   ABERLE, H., H. SCHWARTZ, AND R. KEMLER. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J. Cell. Biochem. 61: 514-523, 1996[Medline].

2.   ACHLER, C., D. FILMER, C. MERTE, AND D. DRENCKHAHN. Role of microtubules in polarized delivery of apical membrane proteins to the brush border of the intestinal epithelium. J. Cell Biol. 109: 179-189, 1989[Abstract/Free Full Text].

3.   ADAMS, A. E., AND J. R. PRINGLE. Relationship of actin and tubulin distribution to bud growth in wild-type and morphogenetic-mutant Saccharomyces cerevisiae. J. Cell Biol. 98: 934-945, 1984[Abstract/Free Full Text].

4.   ADAMS, C. L., W. J. NELSON, AND S. J. SMITH. Quantitative analysis of cadherin-catenin-actin reorganization during development of cell-cell adhesion. J. Cell Biol. 135: 1899-1911, 1996[Abstract/Free Full Text].

5.   AGHIB, D. F., AND P. D. MCCREA. The E-cadherin complex contains the src substrate p120. Exp. Cell Res. 218: 359-369, 1995[Medline].

6.   AL-AWQATI, Q. Plasticity in epithelial polarity of renal intercalated cells: targeting of the H⁺-ATPase and band 3. Am. J. Physiol. 270 (Cell Physiol. 39): C1571-C1580, 1996.

7.   ANDERSON, J. M., AND C. M. VAN ITALLIE. Tight junctions and the molecular basis for regulation of paracellular permeability. Am. J. Physiol. 269(Gastrointest. Liver Physiol. 32): G467-G475, 1995[Abstract/Free Full Text].

8.   APODACA, G., M. H. CARDONE, S. W. WHITEHEART, B. R. DASGUPTA, AND K. E. MOSTOV. Reconstitution of transcytosis in SLO-permeabilized MDCK cells: existence of an NSF-dependent fusion mechanism with the apical surface of MDCK cells. EMBO J. 15: 1471-1481, 1996[Medline].

9.   ARNESON, L. S., AND J. MILLER. Efficient endosomal localization of major histocompatibility complex class II-invariant chain complexes requires multimerization of the invariant chain targeting sequence. J. Cell Biol. 129: 1217-1228, 1995[Abstract/Free Full Text].

10.   AROETI, B., P. A. KOSEN, I. D. KUNTZ, F. E. COHEN, AND K. E. MOSTOV. Mutational and secondary structural analysis of the basolateral sorting signal of the polymeric immunoglobulin receptor. J. Cell Biol. 123: 1149-1160, 1993[Abstract/Free Full Text].

11.   AROETI, B., AND K. E. MOSTOV. Polarized sorting of the polymeric immunoglobulin receptor in the exocytotic and endocytotic pathways is controlled by the same amino acids. EMBO J. 13: 2297-2304, 1994[Medline].

12.   ARREAZA, G., AND D. A. BROWN. Sorting and intracellular trafficking of a glycosylphosphatidylinositol-anchored protein and two hybrid transmembrane proteins with the same ectodomain in Madin-Darby canine kidney epithelial cells. J. Biol. Chem. 270: 23641-23647, 1995[Abstract/Free Full Text].

13.   BACALLAO, R., C. ANTONY, C. DOTTI, E. KARSENTI, E. H. STELZER, AND K. SIMONS. The subcellular organization of Madin-Darby canine kidney cells during the formation of a polarized epithelium. J. Cell Biol. 109: 2817-2832, 1989[Abstract/Free Full Text].

14.   BALCAROVA-STANDER, J., S. E. PFEIFFER, S. D. FULLER, AND K. SIMONS. Development of cell surface polarity in the epithelial Madin-Darby canine kidney (MDCK) cell line. EMBO J. 3: 2687-2694, 1984.

15.   BALDA, M. S., J. A. WHITNEY, C. FLORES, S. GONZALEZ, M. CEREIJIDO, AND K. MATTER. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J. Cell Biol. 134: 1031-1049, 1996[Abstract/Free Full Text].

16.   BARTH, A. I., I. S. NATHKE, AND W. J. NELSON. Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Curr. Opin. Cell Biol. 9: 683-690, 1997[Medline].

17.   BARTLES, J. R., H. M. FERACCI, B. STIEGER, AND A. L. HUBBARD. Biogenesis of the rat hepatocyte plasma membrane in vivo: comparison of the pathways taken by apical and basolateral proteins using subcellular fractionation. J. Cell Biol. 105: 1241-1251, 1987[Abstract/Free Full Text].

18.   BAUMERT, M., P. R. MAYCOX, F. NAVONE, P. DE CAMILLI, AND R. JAHN. Synaptobrevin: an integral membrane protein of 18,000 daltons present in small synaptic vesicles of rat brain. EMBO J. 8: 379-384, 1989[Medline].

19.   BECK, K. A., AND W. J. NELSON. The spectrin-based membrane skeleton as a membrane protein-sorting machine. Am. J. Physiol. 270(Cell Physiol. 39): C1263-C1270, 1996[Abstract/Free Full Text].

20.   BENNETT, M. K., N. CALAKOS, AND R. H. SCHELLER. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257: 255-259, 1992[Abstract/Free Full Text].

21.   BENNETT, M. K., AND J. E. GARCIA. -ARRARAS, L. A. ELFERINK, K. PETERSON, A. M. FLEMING, C. D. HAZUKA, AND R. H. SCHELLER. The syntaxin family of vesicular transport receptors. Cell 74: 863-873, 1993[Medline].

22.   BENNETT, V.. Spectrin-based membrane skeleton: a multipotential adaptor between plasma membrane and cytoplasm. Physiol Rev. 70: 1029-1065, 1990[Free Full Text].

23.   BLOCK, M. R., B. S. GLICK, C. A. WILCOX, F. T. WIELAND, AND J. E. ROTHMAN. Purification of an N-ethylmaleimide-sensitive protein catalyzing vesicular transport. Proc. Natl. Acad. Sci. USA 85: 7852-7856, 1988[Abstract/Free Full Text].

24.   BLOOM, G. S., AND L. S. B. GOLDSTEIN. Cruising along microtubule highways: how membranes move through the secretory pathway. J. Cell Biol. 140: 1277-1280, 1998[Free Full Text].

25.   BOCK, J. B., J. KLUMPERMAN, S. DAVANGER, AND R. H. SCHELLER. Syntaxin 6 functions in trans-Golgi network vesicle trafficking. Mol. Biol. Cell 8: 1261-1271, 1997[Abstract].

26.   BOCK, J. B., R. C. LIN, AND R. H. SCHELLER. A new syntaxin family member implicated in targeting of intracellular transport vesicles. J. Biol. Chem. 271: 17961-17965, 1996[Abstract/Free Full Text].

27.   BOLL, W., H. OHNO, Z. SONGYANG, I. RAPOPORT, L. C. CANTLEY, J. S. BONIFACINO, AND T. KIRCHHAUSEN. Sequence requirements for the recognition of tyrosine-based endocytic signals by clathrin AP-2 complexes. EMBO J. 15: 5789-5795, 1996[Medline].

28.   BOLL, W., J. S. PARTIN, A. I. KATZ, M. J. CAPLAN, AND J. D. JAMIESON. Distinct pathways for basolateral targeting of membrane and secretory proteins in polarized epithelial cells. Proc. Natl. Acad. Sci. USA 88: 8592-8596, 1991[Abstract/Free Full Text].

29.   BOYER, J. L., AND C. J. SOROKA. Vesicle targeting to the apical domain regulates bile excretory function in isolated rat hepatocyte couplets. Gastroenterology 109: 1600-1611, 1995[Medline].

30.   BRADY-KALNAY, S. M., D. L. RIMM, AND N. K. TONKS. Receptor protein tyrosine phosphatase PTPmu associates with cadherins and catenins in vivo. J. Cell Biol. 130: 977-986, 1995.

31.   BRAUN, J. E., B. A. FRITZ, S. M. WONG, AND A. W. LOWE. Identification of a vesicle-associated membrane protein (VAMP)-like membrane protein in zymogen granules of the rat exocrine pancreas. J. Biol. Chem. 269: 5328-5335, 1994[Abstract/Free Full Text].

32.   BREITFELD, P. P., W. C. MCKINNON, AND K. E. MOSTOV. Effect of nocodazole on vesicular traffic to the apical and basolateral surfaces of polarized MDCK cells. J. Cell Biol. 111: 2365-2373, 1990[Abstract/Free Full Text].

33.   BRENNWALD, P., B. KEARNS, K. CHAMPION, S. KERANEN, V. BANKAITIS, AND P. NOVICK. Sec9 is a SNAP-25-like component of a yeast SNARE complex that may be the effector of Sec4 function in exocytosis. Cell 79: 245-258, 1994[Medline].

34.   BRETSCHER, A.. Fimbrin is a cytoskeletal protein that cross-links F-actin in vitro. Proc. Natl. Acad. Sci. USA 78: 6849-6853, 1981[Abstract/Free Full Text].

35.   BRETSCHER, A., B. DREES, E. HARSAY, D. SCHOTT, AND T. WANG. What are the basic functions of microfilaments? Insights from studies in budding yeast. J. Cell Biol. 126: 821-825, 1994[Free Full Text].

36.   BRETSCHER, A., AND K. WEBER. Fimbrin, a new microfilament-associated protein present in microvilli and other cell surface structures. J. Cell Biol. 86: 335-340, 1980[Abstract/Free Full Text].

37.   BRETSCHER, A., AND K. WEBER. Villin is a major protein of the microvillus cytoskeleton which binds both G and F actin in a calcium-dependent manner. Cell 20: 839-847, 1980[Medline].

38.   BREWER, C. B., AND M. G. ROTH. A single amino acid change in the cytoplasmic domain alters the polarized delivery of influenza virus hemagglutinin. J. Cell Biol. 114: 413-421, 1991[Abstract/Free Full Text].

39.   BROWN, D., AND J. L. STOW. Protein trafficking and polarity in kidney epithelium: from cell biology to physiology. Physiol. Rev. 76: 245-297, 1996[Abstract/Free Full Text].

40.   BROWN, D. A., B. CRISE, AND J. K. ROSE. Mechanism of membrane anchoring affects polarized expression of two proteins in MDCK cells. Science 245: 1499-1501, 1989[Abstract/Free Full Text].

41.   BROWN, D. A., AND J. K. ROSE. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68: 533-544, 1992[Medline].

42.   BROWN, D. A., AND A. A. SELYANKO. Membrane currents underlying the cholinergic slow excitatory postsynaptic potential in the rat sympathetic ganglion. J. Physiol (Lond.) 365: 365-387, 1985[Abstract/Free Full Text].

43.   BURRIDGE, K., AND W. M. CHRZANOWSKA. Focal adhesions, contractility, and signaling. Annu. Rev. Cell Dev. Biol. 12: 463-518, 1996.[Medline]

44.   BURRIDGE, K., AND P. MANGEAT. An interaction between vinculin and talin. Nature 308: 744-746, 1984[Medline].

45.   BURRIDGE, K., C. E. TURNER, AND L. H. ROMER. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J. Cell Biol. 119: 893-903, 1992[Abstract/Free Full Text].

46.   CALAKOS, N., M. K. BENNETT, K. E. PETERSON, AND R. H. SCHELLER. Protein-protein interactions contributing to the specificity of intracellular vesicular trafficking. Science 263: 1146-1149, 1994[Abstract/Free Full Text].

47.   CALAKOS, N., AND R. H. SCHELLER. Synaptic vesicle biogenesis, docking, and fusion: a molecular description. Physiol. Rev. 76: 1-29, 1996[Abstract/Free Full Text].

48.   CALHOUN, B. C., AND J. R. GOLDENRING. Two Rab proteins, vesicle-associated membrane protein 2 (VAMP-2) and secretory carrier membrane proteins (SCAMPs), are present on immunoisolated parietal cell tubulovesicles. Biochem. J. 325: 559-564, 1997.

49.   CARBONI, J. M., K. A. CONZELMAN, R. A. ADAMS, D. A. KAISER, T. D. POLLARD, AND M. S. MOOSEKER. Structural and immunological characterization of the myosin-like 110-kDa subunit of the intestinal microvillar 110K-calmodulin complex: evidence for discrete myosin head and calmodulin-binding domains. J. Cell Biol. 107: 1749-1757, 1988[Abstract/Free Full Text].

50.   CEREIJIDO, M., AND L. GONZALEZ. -MARISCAL, R. G. CONTRERAS, J. M. GALLARDO, R. GARCIA-VILLEGAS, AND J. VALDES. The making of a tight junction. J. Cell Sci. Suppl. 17: 127-132, 1993[Medline].

51.   CHAPMAN, E. R., S. AN, N. BARTON, AND R. JAHN. SNAP-25, a t-SNARE which binds to both syntaxin and synaptobrevin via domains that may form coiled coils. J. Biol. Chem. 269: 27427-27432, 1994[Abstract/Free Full Text].

52.   CHAVRIER, P., M. VINGRON, C. SANDER, K. SIMONS, AND M. ZERIAL. Molecular cloning of YPT1/SEC4-related cDNAs from an epithelial cell line. Mol. Cell. Biol. 10: 6578-6585, 1990[Abstract/Free Full Text].

53.   CHRZANOWSKA, W. M., AND K. BURRIDGE. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133: 1403-1415, 1996[Abstract/Free Full Text].

54.   CLARK, E. A., AND J. S. BRUGGE. Integrins and signal transduction pathways: the road taken. Science 268: 233-239, 1995[Abstract/Free Full Text].

55.   CLARK, E. A., S. J. SHATTIL, M. H. GINSBERG, J. BOLEN, AND J. S. BRUGGE. Regulation of the protein tyrosine kinase pp72syk by platelet agonists and the integrin alpha IIb beta 3. J. Biol. Chem. 269: 28859-28864, 1994[Abstract/Free Full Text].

56.   CLARY, D. O., I. C. GRIFF, AND J. E. ROTHMAN. SNAPs, a family of NSF attachment proteins involved in intracellular membrane fusion in animals and yeast. Cell 61: 709-721, 1990[Medline].

57.   CLAUDE, P.. Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens. J. Membr. Biol. 39: 219-232, 1978[Medline].

58.   COBB, B. S., M. D. SCHALLER, T. H. LEU, AND J. T. PARSONS. Stable association of pp60src and pp59fyn with the focal adhesion-associated protein tyrosine kinase, pp125FAK. Mol. Cell. Biol. 14: 147-155, 1994[Abstract/Free Full Text].

59.   COLE, N. B., N. SCIAKY, A. MAROTTA, J. SONG, AND J. LIPPINCOTT. -SCHWARTZ. Golgi dispersal during microtubule disruption: regeneration of Golgi stacks at peripheral endoplasmic reticulum exit sites. Mol. Biol. Cell 7: 631-650, 1996[Abstract].

60.   COLLAWN, J. F., M. STANGEL, L. A. KUHN, V. ESEKOGWU, S. Q. JING, I. S. TROWBRIDGE, AND J. A. TAINER. Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell 63: 1061-1072, 1990[Medline].

61.   COLUCCIO, L. M., AND A. BRETSCHER. Mapping of the microvillar 110K-calmodulin complex: calmodulin-associated or -free fragments of the 110-kDa polypeptide bind F-actin and retain ATPase activity. J. Cell Biol. 106: 367-373, 1988[Abstract/Free Full Text].

62.   COSTA DE BEAUREGARD, M. A., E. PRINGAULT, S. ROBINE, AND D. LOUVARD. Suppression of villin expression by antisense RNA impairs brush border assembly in polarized epithelial intestinal cells. EMBO J. 14: 409-421, 1995.

63.   COWLES, C. R., G. ODORIZZI, G. S. PAYNE, AND S. D. EMR. The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell 91: 109-118, 1997[Medline].

64.   DANIELSEN, E. M.. Involvement of detergent-insoluble complexes in the intracellular transport of intestinal brush border enzymes. Biochemistry 34: 1596-1605, 1995[Medline].

65.   DARSOW, T., S. E. RIEDER, AND S. D. EMR. A multispecificity syntaxin homologue, Vam3p, essential for autophagic and biosynthetic protein transport to the vacuole. J. Cell Biol. 138: 517-529, 1997[Abstract/Free Full Text].

66.   DE ALMEIDA, J. B., J. DOHERTY, D. A. AUSIELLO, AND J. L. STOW. Binding of the cytosolic p200 protein to Golgi membranes is regulated by heterotrimeric G proteins. J. Cell Sci. 106: 1239-1248, 1993[Abstract].

67.   DE ALMEIDA, J. B., AND J. L. STOW. Disruption of microtubules alters polarity of basement membrane proteoglycan secretion in epithelial cells. Am. J. Physiol. 261(Cell Physiol. 30): C691-C700, 1991.

68.   DE CAMILLI, P., AND K. TAKEI. Molecular mechanisms in synaptic vesicle endocytosis and recycling. Neuron 16: 481-486, 1996[Medline].

69.   DE CAMILLI, P., K. TAKEI, AND P. S. MCPHERSON. The function of dynamin in endocytosis. Curr. Opin. Neurobiol. 5: 559-565, 1995[Medline].

70.   DEDHAR, S., AND G. E. HANNIGAN. Integrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr. Opin. Cell Biol. 8: 657-669, 1996[Medline].

71.   DELGROSSI, M.-H., L. BREUZA, C. MIRRE, P. CHAVRIER, AND A. LE BIVIC. Human syntaxin 3 is localized apically in human intestinal cells. J. Cell Sci. 110: 2207-2214, 1997[Abstract].

72.   DELL'ANGELICA, E. C., J. KLUMPERMAN, W. STOORVOGEL, AND J. S. BONIFACINO. Association of the AP-3 adaptor complex with clathrin. Science 280: 431-434, 1998[Abstract/Free Full Text].

73.   DELL'ANGELICA, E. C., H. OHNO, C. E. OOI, E. RABINOVICH, K. W. ROCHE, AND J. S. BONIFACINO. AP-3: an adaptor-like protein complex with ubiquitous expression. EMBO J. 16: 917-928, 1997[Medline].

74.   DELL'ANGELICA, E. C., C. E. OOI, AND J. S. BONIFACINO. Beta3A-adaptin, a subunit of the adaptor-like complex AP-3. J. Biol. Chem. 272: 15078-15084, 1997[Abstract/Free Full Text].

75.   DIAMOND, J. M.. Twenty-first Bowditch lecture. The epithelial junction: bridge, gate, and fence. Physiologist 20: 10-18, 1977[Medline].

76.   DRAGSTEN, P. R., R. BLUMENTHAL, AND J. S. HANDLER. Membrane asymmetry in epithelia: is the tight junction a barrier to diffusion in the plasma membrane? Nature 294: 718-722, 1981.

77.   EBERLE, W., C. SANDER, W. KLAUS, B. SCHMIDT, K. VON FIGURA, AND C. PETERS. The essential tyrosine of the internalization signal in lysosomal acid phosphatase is part of a -turn. Cell 67: 1203-1209, 1991[Medline].

78.   EILERS, U., J. KLUMPERMAN, AND H. P. HAURI. Nocodazole, a microtubule-active drug, interferes with apical protein delivery in cultured intestinal epithelial cells (Caco-2). J. Cell Biol. 108: 13-22, 1989[Abstract/Free Full Text].

79.   ELFERINK, L. A., W. S. TRIMBLE, AND R. H. SCHELLER. Two vesicle-associated membrane protein genes are differentially expressed in the rat central nervous system. J. Biol. Chem. 264: 11061-11064, 1989[Abstract/Free Full Text].

80.   EZZELL, R. M., J. LEUNG, K. COLLINS, M. M. CHAFEL, T. J. CARDOZO, AND P. T. MATSUDAIRA. Expression and localization of villin, fimbrin, and myosin I in differentiating mouse F9 teratocarcinoma cells. Dev Biol. 151: 575-585, 1992[Medline].

81.   FANNING, A. S., AND J. M. ANDERSON. Protein-protein interactions: PDZ domain networks. Curr. Biol. 6: 1385-1388, 1996[Medline].

82.   FATH, K. R., AND D. R. BURGESS. Golgi-derived vesicles from developing epithelial cells bind actin filaments and possess myosin-I as a cytoplasmically oriented peripheral membrane protein. J. Cell Biol. 120: 117-127, 1993[Abstract/Free Full Text].

83.   FIEDLER, K., F. LAFONT, R. G. PARTON, AND K. SIMONS. Annexin XIIIb: a novel epithelial specific annexin is implicated in vesicular traffic to the apical plasma membrane. J. Cell Biol. 128: 1043-1053, 1995[Abstract/Free Full Text].

84.   FIEDLER, K., R. G. PARTON, R. KELLNER, T. ETZOLD, AND K. SIMONS. VIP36, a novel component of glycolipid rafts and exocytic carrier vesicles in epithelial cells. EMBO J. 13: 1729-1740, 1994[Medline].

85.   FIEDLER, K., AND K. SIMONS. The role of N-glycans in the secretory pathway. Cell 81: 309-312, 1995[Medline].

86.   FIEDLER, K., AND K. SIMONS. Characterization of VIP36, an animal lectin homologous to leguminous lectins. J. Cell Sci. 109: 271-276, 1996[Abstract].

87.   FINGER, F. P., T. E. HUGHES, AND P. NOVICK. Sec3p is a spatial landmark for polarized secretion in budding yeast. Cell 92: 559-571, 1998[Medline].

88.   FRA, A. M., E. WILLIAMSON, K. SIMONS, AND R. G. PARTON. Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J. Biol. Chem. 269: 30745-30748, 1994[Abstract/Free Full Text].

89.   FRANCK, Z., M. FOOTER, AND A. BRETSCHER. Microinjection of villin into cultured cells induces rapid and long-lasting changes in cell morphology but does not inhibit cytokinesis, cell motility, or membrane ruffling. J. Cell Biol. 111: 2475-2485, 1990[Abstract/Free Full Text].

90.   FRANKI, N., F. MACALUSO, Y. GAO, AND R. M. HAYS. Vesicle fusion proteins in rat inner medullary collecting duct and amphibian bladder. Am. J. Physiol. 268(Cell Physiol. 37): C792-C797, 1995[Abstract/Free Full Text].

91.   FRANKI, N., F. MACALUSO, W. SCHUBERT, L. GUNTHER, AND R. M. HAYS. Water channel-carrying vesicles in the rat IMCD contain cellubrevin. Am. J. Physiol. 269(Cell Physiol. 38): C797-C801, 1995[Abstract/Free Full Text].

92.   FRIEDERICH, E., C. HUET, M. ARPIN, AND D. LOUVARD. Villin induces microvilli growth and actin redistribution in transfected fibroblasts. Cell 59: 461-475, 1989[Medline].

93.   FUJIMOTO, K.. Freeze-fracture replica electron microscopy combined with SDS digestion for cytochemical labeling of integral membrane proteins. Application to the immunogold labeling of intercellular junctional complexes. J. Cell Sci. 108: 3443-3449, 1995[Abstract].

94.   FUJITA, H., P. L. TUMA, C. M. FINNEGAN, L. LOCCO, AND A. L. HUBBARD. Endogenous syntaxins 2, 3 and 4 exhibit distinct but overlapping patterns of expression at the hepatocyte plasma membrane. Biochem. J. 329: 527-538, 1998.

95.   FUJITA, Y., T. SASAKI, K. FUKUI, H. KOTANI, T. KIMURA, Y. HATA, T. C. SUDHOF, R. H. SCHELLER, AND Y. TAKAI. Phosphorylation of Munc-18/n-Sec1/rbSec1 by protein kinase C: its implication in regulating the interaction of Munc-18/n-Sec1/rbSec1 with syntaxin. J. Biol. Chem. 271: 7265-7268, 1996[Abstract/Free Full Text].

96.   FURUSE, M., T. HIRASE, M. ITOH, A. NAGAFUCHI, S. YONEMURA, S. TSUKITA, AND S. TSUKITA. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123: 1777-1788, 1993[Abstract/Free Full Text].

97.   FURUSE, M., M. ITOH, T. HIRASE, A. NAGAFUCHI, S. YONEMURA, S. TSUKITA, AND S. TSUKITA. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J. Cell Biol. 127: 1617-1626, 1994[Abstract/Free Full Text].

98.   FUTTER, C. E., C. N. CONNOLLY, D. F. CUTLER, AND C. R. HOPKINS. Newly synthesized transferrin receptors can be detected in the endosome before they appear on the cell surface. J. Biol. Chem. 270: 10999-11003, 1995[Abstract/Free Full Text].

99.   GAISANO, H. Y., M. GHAI, P. N. MALKUS, L. SHEU, A. BOUQUILLON, M. K. BENNETT, AND W. S. TRIMBLE. Distinct cellular locations of the syntaxin family of proteins in rat pancreatic acinar cells. Mol. Biol. Cell 7: 2019-2027, 1996[Abstract].

100.   GAISANO, H. Y., L. SHEU, J. K. FOSKETT, AND W. S. TRIMBLE. Tetanus toxin light chain cleaves a vesicle-associated membrane protein (VAMP) isoform 2 in rat pancreatic zymogen granules and inhibits enzyme secretion. J. Biol. Chem. 269: 17062-17066, 1994[Abstract/Free Full Text].

101.   GAISANO, H. Y., L. SHEU, G. GRONDIN, M. GHAI, A. BOUQUILLON, A. LOWE, A. BEAUDOIN, AND W. S. TRIMBLE. The vesicle-associated membrane protein family of proteins in rat pancreatic and parotid acinar cells. Gastroenterology 111: 1661-1669, 1996[Medline].

102.   GAISANO, H. Y., L. SHEU, P. P. WONG, A. KLIP, AND W. S. TRIMBLE. SNAP-23 is located in the basolateral plasma membrane of rat pancreatic acinar cells. FEBS Lett. 414: 298-302, 1997[Medline].

103.   GALLI, T., E. P. GARCIA, O. MUNDIGL, T. J. CHILCOTE, AND P. DE CAMILLI. v- and t-SNAREs in neuronal exocytosis: a need for additional components to define sites of release. Neuropharmacology 34: 1351-1360, 1995[Medline].

104.   GALLI, T., A. ZAHRAOUI, V. V. VAIDYANATHAN, G. RAPOSO, J. M. TIAN, M. KARIN, H. NIEMANN, AND D. LOUVARD. A novel tetanus neurotoxin insensitive vesicle associated membrane protein (TI-VAMP) in SNARE complexes of the apical plasma membrane of epithelial cells. Mol. Biol. Cell. 9: 1437-1524, 1998[Abstract/Free Full Text].

105.   GARCIA, E. P., E. GATTI, M. BUTLER, J. BURTON, AND P. DE CAMILLI. A rat brain Sec1 homologue related to Rop and UNC18 interacts with syntaxin. Proc. Natl. Acad. Sci. USA 91: 2003-2007, 1994[Abstract/Free Full Text].

106.   GARCIA, E. P., P. S. MCPHERSON, T. J. CHILCOTE, K. TAKEI, AND P. DE CAMILLI. rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin. J. Cell Biol. 129: 105-120, 1995[Abstract/Free Full Text].

107.   GARCIA, M., C. MIRRE, A. QUARONI, H. REGGIO, AND A. LE BIVIC. GPI-anchored proteins associate to form microdomains during their intracellular transport in Caco-2 cells. J. Cell Sci. 104: 1281-1290, 1993[Abstract].

108.   GEFFEN, I., C. FUHRER, B. LEITINGER, M. WEISS, K. HUGGEL, G. GRIFFITHS, AND M. SPIESS. Related signals for endocytosis and basolateral sorting of the asialoglycoprotein receptor. J. Biol. Chem. 268: 20772-20777, 1993[Abstract/Free Full Text].

109.   GILBERT, T., A. LE BIVIC, A. QUARONI, AND E. RODRIGUEZ. -BOULAN. Microtubular organization and its involvement in the biogenetic pathways of plasma membrane proteins in Caco-2 intestinal epithelial cells. J. Cell Biol. 113: 275-288, 1991[Abstract/Free Full Text].

110.   GILBERT, T., AND E. RODRIGUEZ. -BOULAN. Induction of vacuolar apical compartments in the Caco-2 intestinal epithelial cell line. J. Cell Sci. 100: 451-458, 1991[Abstract/Free Full Text].

111.   GILMORE, A. P., AND L. H. ROMER. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol. Biol. Cell 7: 1209-1224, 1996[Abstract].

112.   GONZALEZ, A., S. NICOVANI, AND F. JUICA. Apical secretion of hepatitis B surface antigen from transfected Madin-Darby canine kidney cells. J. Biol. Chem. 268: 6662-6667, 1993[Abstract/Free Full Text].

113.   GOTTLIEB, T. A., I. E. IVANOV, M. ADESNIK, AND D. D. SABATINI. Actin microfilaments play a critical role in endocytosis at the apical but not the basolateral surface of polarized epithelial cells. J. Cell Biol. 120: 695-710, 1993[Abstract/Free Full Text].

114.   GOUD, B., A. SALMINEN, N. C. WALWORTH, AND P. J. NOVICK. A GTP-binding protein required for secretion rapidly associates with secretory vesicles and the plasma membrane in yeast. Cell 53: 753-768, 1988[Medline].

115.   GOVINDAN, B., AND P. NOVICK. Development of cell polarity in budding yeast. J. Exp. Zool. 273: 401-424, 1995[Medline].

116.   GREEN, R. F., H. K. MEISS, AND E. RODRIGUEZ. -BOULAN. Glycosylation does not determine segregation of viral envelope proteins in the plasma membrane of epithelial cells. J. Cell Biol. 89: 230-239, 1981[Abstract/Free Full Text].

117.   GRINDSTAFF, K. K., R. L. BACALLAO, AND W. J. NELSON. Apiconuclear organization of microtubules does not specify protein delivery from the trans-Golgi network to different membrane domains in polarized epithelial cells. Mol. Biol. Cell 9: 685-699, 1998[Abstract/Free Full Text].

118.   GRINDSTAFF, K. K., C. YEAMAN, N. ANANDASABAPATHY, S.-C. HSU, AND E. RODRIGUEZ. -BOULAN, R. H. SCHELLER, AND W. J. NELSON. Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in polarized epithelial cells. Cell 93: 731-740, 1998[Medline].

119.   GUO, W., D. ROTH, E. GATTI, P. DE CAMILLI, AND P. NOVICK. Identification and characterization of homologues of the Exocyst component Sec10p. FEBS Lett. 404: 135-139, 1997[Medline].

120.   GUT, A., F. KAPPELER, N. HYKA, M. S. BALDA, H.-P. HAURI, AND K. MATTER. Carbohydrate-mediated Golgi to cell surface transport and apical targeting of membrane proteins. EMBO J. 17: 1919-1929, 1998[Medline].

121.   HAAS, A., AND W. WICKNER. Homotypic vacuole fusion requires Sec17p (yeast alpha-SNAP) and Sec18p (yeast NSF). EMBO J. 15: 3296-3305, 1996[Medline].

122.   HAMMERTON, R. W., K. A. KRZEMINSKI, R. W. MAYS, T. A. RYAN, D. A. WOLLNER, AND W. J. NELSON. Mechanism for regulating cell surface distribution of Na⁺,K⁺-ATPase in polarized epithelial cells. Science 254: 847-850, 1991[Abstract/Free Full Text].

123.   HANKS, S. K., AND T. R. POLTE. Signaling through focal adhesion kinase. Bioessays 19: 137-145, 1997[Medline].

124.   HANNAN, L. A., M. P. LISANTI, AND E. RODRIGUEZ. -BOULAN, AND M. EDIDIN. Correctly sorted molecules of a GPI-anchored protein are clustered and immobile when they arrive at the apical surface of MDCK cells. J. Cell Biol. 120: 353-358, 1993[Abstract/Free Full Text].

125.   HARTER, C., AND I. MELLMAN. Transport of the lysosomal membrane glycoprotein lgp120 (lgp-A) to lysosomes does not require appearance on the plasma membrane. J. Cell Biol. 117: 311-325, 1992[Abstract/Free Full Text].

126.   HASKINS, J., L. GU, E. S. WITTCHEN, J. HIBBARD, AND B. R. STEVENSON. ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J. Cell Biol. 141: 199-208, 1998[Abstract/Free Full Text].

127.   HATA, Y., C. A. SLAUGHTER, AND T. C. SUDHOF. Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 366: 347-351, 1993[Medline].

128.   HATA, Y., AND T. C. SUDHOF. A novel ubiquitous form of Munc-18 interacts with multiple syntaxins. Use of the yeast two-hybrid system to study interactions between proteins involved in membrane traffic. J. Biol. Chem. 270: 13022-13028, 1995[Abstract/Free Full Text].

129.   HAY, J. C., D. S. CHAO, C. S. KUO, AND R. H. SCHELLER. Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells. Cell 89: 149-158, 1997[Medline].

130.   HAY, J. C., H. HIRLING, AND R. H. SCHELLER. Mammalian vesicle trafficking proteins of the endoplasmic reticulum and Golgi apparatus. J. Biol. Chem. 271: 5671-5679, 1996[Abstract/Free Full Text].

131.   HAYS, R. M., J. CONDEELIS, Y. GAO, H. SIMON, G. DING, AND N. FRANKI. The effect of vasopressin on the cytoskeleton of the epithelial cell. Pediatr. Nephrol. 7: 672-679, 1993[Medline].

132.   HAYS, R. M., N. FRANKI, H. SIMON, AND Y. GAO. Antidiuretic hormone and exocytosis: lessons from neurosecretion. Am. J. Physiol. 267(Cell Physiol. 36): C1507-C1524, 1994[Abstract/Free Full Text].

133.   HAZUKA, C. D., S. C. HSU, AND R. H. SCHELLER. Characterization of a cDNA encoding a subunit of the rat brain rsec6/8 complex. Gene 187: 67-73, 1997[Medline].

134.   HEILKER, R., AND U. MANNING. -KRIEG, J. F. ZUBER, AND M. SPIESS. In vitro binding of clathrin adaptors to sorting signals correlates with endocytosis and basolateral sorting. EMBO J. 15: 2893-2899, 1996[Medline].

135.   HEINTZELMAN, M. B., AND M. S. MOOSEKER. Structural and compositional analysis of early stages in microvillus assembly in the enterocyte of the chick embryo. Differentiation 43: 175-182, 1990[Medline].

136.   HERZLINGER, D. A., AND G. K. OJAKIAN. Studies on the development and maintenance of epithelial cell surface polarity with monoclonal antibodies. J. Cell Biol. 98: 1777-1787, 1984[Abstract/Free Full Text].

137.   HILDEBRAND, J. D., M. D. SCHALLER, AND J. T. PARSONS. Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions. J. Cell Biol. 123: 993-1005, 1993[Abstract/Free Full Text].

138.   HILDEBRAND, J. D., M. D. SCHALLER, AND J. T. PARSONS. Paxillin, a tyrosine phosphorylated focal adhesion-associated protein, binds to the carboxyl terminal domain of focal adhesion kinase. Mol. Biol. Cell 6: 637-647, 1995[Abstract].

139.   HILDEBRAND, J. D., J. M. TAYLOR, AND J. T. PARSONS. An SH₃ domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase. Mol. Cell. Biol. 16: 3169-3178, 1996[Abstract].

140.   HINCK, L., I. S. NATHKE, J. PAPKOFF, AND W. J. NELSON. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J. Cell Biol. 125: 1327-1340, 1994[Abstract/Free Full Text].

141.   HIRANO, S., A. NOSE, K. HATTA, A. KAWAKAMI, AND M. TAKEICHI. Calcium-dependent cell-cell adhesion molecules (cadherins): subclass specificities and possible involvement of actin bundles. J. Cell Biol. 105: 2501-2510, 1987[Abstract/Free Full Text].

142.   HIRLING, H., AND R. H. SCHELLER. Phosphorylation of synaptic vesicle proteins: modulation of the alpha SNAP interaction with the core complex. Proc. Natl. Acad. Sci. USA 93: 11945-11949, 1996[Abstract/Free Full Text].

143.   HIROKAWA, N., R. E. CHENEY, AND M. WILLARD. Location of a protein of the fodrin-spectrin-TW260/240 family in the mouse intestinal brush border. Cell 32: 953-965, 1983[Medline].

144.   HIROKAWA, N., AND J. E. HEUSER. Quick-freeze, deep-etch visualization of the cytoskeleton beneath surface differentiations of intestinal epithelial cells. J. Cell Biol. 91: 399-409, 1981[Abstract/Free Full Text].

145.   HIROKAWA, N., L. G. TILNEY, K. FUJIWARA, AND J. E. HEUSER. Organization of actin, myosin, and intermediate filaments in the brush border of intestinal epithelial cells. J. Cell Biol. 94: 425-443, 1982[Abstract/Free Full Text].

146.   HÖNING, S., J. GRIFFITH, H. J. GEUZE, AND W. HUNZIKER. The tyrosine-based lysosomal targeting signal in lamp-1 mediates sorting into Golgi-derived clathrin-coated vesicles. EMBO J. 15: 5230-5239, 1996[Medline].

147.   HÖNING, S., AND W. HUNZIKER. Cytoplasmic determinants involved in direct lysosomal sorting, endocytosis, and basolateral targeting of rat lgp120 (lamp-I) in MDCK cells. J. Cell Biol. 128: 321-332, 1995[Abstract/Free Full Text].

148.   HÖNING, S., I. V. SANDOVAL, AND K. VON FIGURA. A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3. EMBO J. 17: 1304-1314, 1998[Medline].

149.   HOPPE, C. A., T. P. CONNOLLY, AND A. L. HUBBARD. Transcellular transport of polymeric IgA in the rat hepatocyte: biochemical and morphological characterization of the transport pathway. J. Cell Biol. 101: 2113-2123, 1985[Abstract/Free Full Text].

150.   HORWITZ, A., K. DUGGAN, C. BUCK, M. C. BECKERLE, AND K. BURRIDGE. Interaction of plasma membrane fibronectin receptor with talin  a transmembrane linkage. Nature 320: 531-533, 1986[Medline].

151.   HOTCHIN, N. A., AND A. HALL. The assembly of integrin adhesion complexes requires both extracellular matrix and intracellular rho/rac GTPases. J. Cell Biol. 131: 1857-1865, 1995[Abstract/Free Full Text].

152.   HSU, S. M., A. WERNER, G. GRIFFITHS, AND L. RAINE. Demonstration of myoglobin in Formalin-fixed renal sections by immunoperoxidase technique. Am. J. Clin. Pathol. 77: 316-319, 1982[Medline].

153.   HU, R. J., S. MOORTHY, AND V. BENNETT. Expression of functional domains of beta G-spectrin disrupts epithelial morphology in cultured cells. J. Cell Biol. 128: 1069-1080, 1995[Abstract/Free Full Text].

154.   HUBBARD, A. L.. Targeting of membrane and secretory proteins to the apical domain in epithelial cells. Semin. Cell Biol. 2: 365-374, 1991[Medline].

155.   HUBER, L. A., S. PIMPLIKAR, R. G. PARTON, H. VIRTA, M. ZERIAL, AND K. SIMONS. Rab8, a small GTPase involved in vesicular traffic between the TGN and the basolateral plasma membrane. J. Cell Biol. 123: 35-45, 1993[Abstract/Free Full Text].

156.   HUGHEY, P. G., R. W. COMPANS, S. L. ZEBEDEE, AND R. A. LAMB. Expression of the influenza A virus M2 protein is restricted to apical surfaces of polarized epithelial cells. J. Virol. 66: 5542-5552, 1992[Abstract/Free Full Text].

157.   HUI, N., N. NAKAMURA, B. SONNICHSEN, D. T. SHIMA, T. NILSSON, AND G. WARREN. An isoform of the Golgi t-SNARE, syntaxin 5, with an endoplasmic reticulum retrieval signal. Mol. Biol. Cell 8: 1777-1787, 1997[Abstract].

158.   HUNZIKER, W., AND C. FUMEY. A di-leucine motif mediates endocytosis and basolateral sorting of macrophage IgG Fc receptors in MDCK cells. EMBO J. 13: 2963-2967, 1994[Medline].

159.   HUNZIKER, W., C. HARTER, K. MATTER, AND I. MELLMAN. Basolateral sorting in MDCK cells requires a distinct cytoplasmic domain determinant. Cell 66: 907-920, 1991[Medline].

160.   HUNZIKER, W., P. MALE, AND I. MELLMAN. Differential microtubule requirements for transcytosis in MDCK cells. EMBO J. 9: 3515-3525, 1990[Medline].

161.   HUNZIKER, W., AND I. MELLMAN. Relationships between sorting in the exocytic and endocytic pathways of MDCK cells. Semin. Cell Biol. 2: 397-410, 1991[Medline].

162.   HYNES, R. O.. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11-25, 1992[Medline].

163.   IKONEN, E., A. J. DE, K. F. FATH, D. R. BURGESS, K. ASHMAN, K. SIMONS, AND J. L. STOW. Myosin II is associated with Golgi membranes: identification of p200 as nonmuscle myosin II on Golgi-derived vesicles. J. Cell Sci. 110: 2155-2164, 1997[Abstract].

164.   IKONEN, E., R. G. PARTON, F. LAFONT, AND K. SIMONS. Analysis of the role of p200-containing vesicles in post-Golgi traffic. Mol. Biol. Cell 7: 961-974, 1996[Abstract].

165.   IKONEN, E., M. TAGAYA, O. ULLRICH, C. MONTECUCCO, AND K. SIMONS. Different requirements for NSF, SNAP, and Rab proteins in apical and basolateral transport in MDCK cells. Cell 81: 571-580, 1995[Medline].

166.   ILIC, D., Y. FURUTA, S. KANAZAWA, N. TAKEDA, K. SOBUE, N. NAKATSUJI, S. NOMURA, J. FUJIMOTO, M. OKADA, AND T. YAMAMOTO. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539-544, 1995[Medline].

167.   ITOH, M., A. NAGAFUCHI, S. YONEMURA, AND T. KITANI. -YASUDA, S. TSUKITA, AND S. TSUKITA. The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J. Cell Biol. 121: 491-502, 1993[Abstract/Free Full Text].

168.   JAGADISH, M. N., J. T. TELLAM, S. L. MACAULAY, K. H. GOUGH, D. E. JAMES, AND C. W. WARD. Novel isoform of syntaxin 1 is expressed in mammalian cells. Biochem. J. 321: 151-156, 1997.

169.   JESAITIS, L. A., AND D. A. GOODENOUGH. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. J. Cell Biol. 124: 949-961, 1994[Abstract/Free Full Text].

170.   JO, I., H. W. HARRIS, R. A. AMENDT, R. R. MAJEWSKI, AND T. G. HAMMOND. Rat kidney papilla contains abundant synaptobrevin protein that participates in the fusion of antidiuretic hormone-regulated water channel-containing endosomes in vitro. Proc. Natl. Acad. Sci. USA 92: 1876-1880, 1995[Abstract/Free Full Text].

171.   JOHNSON, R. P., AND S. W. CRAIG. F-actin binding site masked by the intramolecular association of vinculin head and tail domains. Nature 373: 261-264, 1995[Medline].

172.   JONES, S. M., J. R. CROSBY, J. SALAMERO, AND K. E. HOWELL. A cytosolic complex of p62 and rab6 associates with TGN38/41 and is involved in budding of exocytic vesicles from the trans-Golgi network. J. Cell Biol. 122: 775-788, 1993[Abstract/Free Full Text].

173.   JONES, S. M., AND K. E. HOWELL. Phosphatidylinositol 3-kinase is required for the formation of constitutive transport vesicles from the TGN. J. Cell Biol. 139: 339-349, 1997[Abstract/Free Full Text].

174.   JONES, S. M., K. E. HOWELL, J. R. HENLEY, H. CAO, AND M. A. MCNIVEN. Role of dynamin in the formation of transport vesicles from the trans-Golgi network. Science 279: 573-577, 1998[Abstract/Free Full Text].

175.   KEE, Y., J. S. YOO, C. D. HAZUKA, K. E. PETERSON, S. C. HSU, AND R. H. SCHELLER. Subunit structure of the mammalian exocyst complex. Proc. Natl. Acad. Sci. USA 94: 14438-14443, 1997[Abstract/Free Full Text].

176.   KELLER, P., AND K. SIMONS. Post-Golgi biosynthetic trafficking. J. Cell Sci. 110: 3001-3009, 1997[Abstract].

177.   KELLER, P., AND K. SIMONS. Cholesterol is required for surface transport of influenza virus hemagglutinin. J. Cell Biol. 140: 1357-1367, 1998[Abstract/Free Full Text].

178.   KELLY, R. B.. Microtubules, membrane traffic, and cell organization. Cell 61: 5-7, 1990[Medline].

179.   KEMLER, R.. Classical cadherins. Semin. Cell Biol. 3: 149-155, 1992[Medline].

180.   KIRCHHAUSEN, T., J. S. BONIFACINO, AND H. RIEZMAN. Linking cargo to vesicle formation: receptor tail interactions with coat proteins. Curr. Opin. Cell Biol. 9: 488-495, 1997[Medline].

181.   KITAGAWA, Y., Y. SANO, M. UEDA, K. HIGASHIO, H. NARITA, M. OKANO, S. MATSUMOTO, AND R. SASAKI. N-glycosylation of erythropoietin is critical for apical secretion by Madin-Darby canine kidney cells. Exp. Cell Res. 213: 449-457, 1994[Medline].

182.   KNUDSEN, K. A., A. P. SOLER, K. R. JOHNSON, AND M. J. WHEELOCK. Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin. J. Cell Biol. 130: 67-77, 1995[Abstract/Free Full Text].

183.   KORNBERG, L., H. S. EARP, J. T. PARSONS, M. SCHALLER, AND R. L. JULIANO. Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J. Biol. Chem. 267: 23439-23442, 1992[Abstract/Free Full Text].

184.   KREIS, T. E.. Role of microtubules in the organisation of the Golgi apparatus. Cell. Motil. Cytoskeleton 15: 67-70, 1990[Medline].

185.   KUNDU, A., R. T. AVALOS, C. M. SANDERSON, AND D. P. NAYAK. Transmembrane domain of influenza virus neuraminidase, a type II protein, possesses an apical sorting signal in polarized MDCK cells. J. Virol. 70: 6508-6515, 1996[Abstract].

186.   KURZCHALIA, T. V., P. DUPREE, R. G. PARTON, R. KELLNER, H. VIRTA, M. LEHNERT, AND K. SIMONS. VIP21, a 21-kD membrane protein is an integral component of trans-Golgi-network-derived transport vesicles. J. Cell Biol. 118: 1003-1014, 1992[Abstract/Free Full Text].

187.   KYPTA, R. M., H. SU, AND L. F. REICHARDT. Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J. Cell Biol. 134: 1519-1529, 1996[Abstract/Free Full Text].

188.   LADINSKY, M. S., J. R. KREMER, P. S. FURCINITTI, J. R. MCINTOSH, AND K. E. HOWELL. HVEM tomography of the trans-Golgi network: structural insights and identification of a lace-like vesicle coat. J. Cell Biol. 127: 29-38, 1994[Abstract/Free Full Text].

189.   LAFONT, F., J. K. BURKHARDT, AND K. SIMONS. Involvement of microtubule motors in basolateral and apical transport in kidney cells. Nature 372: 801-803, 1994[Medline].

190.   LE BIVIC, A., A. QUARONI, B. NICHOLS, AND E. RODRIGUEZ. -BOULAN. Biogenetic pathways of plasma membrane proteins in Caco-2, a human intestinal epithelial cell line. J. Cell Biol. 111: 1351-1361, 1990[Abstract/Free Full Text].

191.   LE BIVIC, A., Y. SAMBUY, A. PATZAK, N. PATIL, M. CHAO, AND E. RODRIGUEZ. -BOULAN. An internal deletion in the cytoplasmic tail reverses the apical localization of human NGF receptor in transfected MDCK cells. J. Cell Biol. 115: 607-618, 1991[Abstract/Free Full Text].

192.   LE BORGNE, R., A. SCHMIDT, F. MAUXION, G. GRIFFITHS, AND B. HOFLACK. Binding of AP-1 Golgi adaptors to membranes requires phosphorylated cytoplasmic domains of the mannose 6-phosphate/insulin-like growth factor II receptor. J. Biol. Chem. 268: 22552-22556, 1993[Abstract/Free Full Text].

193.   LE GALL, A. H., S. K. POWELL, C. A. YEAMAN, AND E. RODRIGUEZ. -BOULAN. The neural cell adhesion molecule expresses a tyrosine-independent basolateral sorting signal. J. Biol. Chem. 272: 4559-4567, 1997[Abstract/Free Full Text].

194.   LEITINGER, B., AND A. HILLE. -REHFELD, AND M. SPIESS. Biosynthetic transport of the asialoglycoprotein receptor H1 to the cell surface occurs via endosomes. Proc. Natl. Acad. Sci. USA 92: 10109-10113, 1995[Abstract/Free Full Text].

195.   LEWIS, J. M., AND M. A. SCHWARTZ. Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol. Biol. Cell 6: 151-160, 1995[Abstract].

196.   LINK, E., L. EDELMANN, J. H. CHOU, T. BINZ, S. YAMASAKI, U. EISEL, M. BAUMERT, T. C. SUDHOF, H. NIEMANN, AND R. JAHN. Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem. Biophys. Res. Commun. 189: 1017-1023, 1992[Medline].

197.   LIPARDI, C., R. MORA, V. COLOMER, S. PALADINO, L. NITSCH, AND E. RODRIGUEZ. -BOULAN, AND C. ZURZOLO. Caveolin transfection results in caveolae formation but not apical sorting of glycosylphosphatidylinositol (GPI)-anchored proteins in epithelial cells. J. Cell Biol. 140: 617-626, 1998[Abstract/Free Full Text].

198.   LIPFERT, L., B. HAIMOVICH, M. D. SCHALLER, B. S. COBB, J. T. PARSONS, AND J. S. BRUGGE. Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. J. Cell Biol. 119: 905-912, 1992[Abstract/Free Full Text].

199.   LISANTI, M. P., I. W. CARAS, M. A. DAVITZ, AND E. RODRIGUEZ. -BOULAN. A glycophospholipid membrane anchor acts as an apical targeting signal in polarized epithelial cells. J. Cell Biol. 109: 2145-2156, 1989[Abstract/Free Full Text].

200.   LO, S. H., Q. C. YU, L. DEGENSTEIN, L. B. CHEN, AND E. FUCHS. Progressive kidney degeneration in mice lacking tensin. J. Cell Biol. 136: 1349-1361, 1997[Abstract/Free Full Text].

201.   LODGE, R., J. P. LALONDE, G. LEMAY, AND E. A. COHEN. The membrane-proximal intracytoplasmic tyrosine residue of HIV-1 envelope glycoprotein is critical for basolateral targeting of viral budding in MDCK cells. EMBO J. 16: 695-705, 1997[Medline].

202.   LOMBARDO, C., D. RIMM, E. KOSLOV, AND J. MORROW. Human recombinant alpha-catenin binds to spectrin (Abstract). Mol. Biol. Cell 5: 47a, 1994.

203.   LOW, S. H., S. J. CHAPIN, T. WEIMBS, L. G. KOMUVES, M. K. BENNETT, AND K. E. MOSTOV. Differential localization of syntaxin isoforms in polarized Madin-Darby canine kidney cells. Mol. Biol. Cell 7: 2007-2018, 1996[Abstract].

204.   LOW, S. H., P. A. ROCHE, H. A. ANDERSON, I. S. VAN, M. ZHANG, K. E. MOSTOV, AND T. WEIMBS. Targeting of SNAP-23 and SNAP-25 in polarized epithelial cells. J. Biol. Chem. 273: 3422-3430, 1998[Abstract/Free Full Text].

205.   MADARA, J. L. Tight junction dynamics: is paracellular transport regulated? Cell 53: 497-498, 1988.

206.   MALHOTRA, V., L. ORCI, B. S. GLICK, M. R. BLOCK, AND J. E. ROTHMAN. Role of an N-ethylmaleimide-sensitive transport component in promoting fusion of transport vesicles with cisternae of the Golgi stack. Cell 54: 221-227, 1988[Medline].

207.   MANDIC, R., W. S. TRIMBLE, AND A. W. LOWE. Tissue-specific alternative RNA splicing of rat vesicle-associated membrane protein-1 (VAMP-1). Gene 199: 173-179, 1997[Medline].

208.   MANDON, B., C. L. CHOU, S. NIELSEN, AND M. A. KNEPPER. Syntaxin-4 is localized to the apical plasma membrane of rat renal collecting duct cells: possible role in aquaporin-2 trafficking. J. Clin. Invest. 98: 906-913, 1996[Medline].

209.   MANDON, B., S. NIELSEN, B. K. KISHORE, AND M. A. KNEPPER. Expression of syntaxins in rat kidney. Am. J. Physiol. 273(Renal Physiol. 42): F718-F730, 1997.

210.   MAPLES, C. J., W. G. RUIZ, AND G. APODACA. Both microtubules and actin filaments are required for efficient postendocytotic traffic of the polymeric immunoglobulin receptor in polarized Madin-Darby canine kidney cells. J. Biol. Chem. 272: 6741-6751, 1997[Abstract/Free Full Text].

211.   MARKS, M. S., H. OHNO, T. KIRCHHAUSEN, AND J. S. BONIFACINO. Protein sorting by tyrosine-based signals: adapting to the Ys and wherefores. Trends Cell Biol. 7: 124-128, 1997.[Medline]

212.   MARKS, M. S., L. WOODRUFF, H. OHNO, AND J. S. BONIFACINO. Protein targeting by tyrosine- and di-leucine-based signals: evidence for distinct saturable components. J. Cell Biol. 135: 341-354, 1996[Abstract/Free Full Text].

213.   MARRS, J. A., AND C. ANDERSSON. -FISONE, M. C. JEONG, L. COHEN-GOULD, C. ZURZOLO, I. R. NABI, E. RODRIGUEZ-BOULAN, AND W. J. NELSON. Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J. Cell Biol. 129: 507-519, 1995[Abstract/Free Full Text].

214.   MARZOLO, M. P., P. BULL, AND A. GONZALEZ. Apical sorting of hepatitis B surface antigen (HBsAg) is independent of N-glycosylation and glycosylphosphatidylinositol-anchored protein segregation. Proc. Natl. Acad. Sci. USA 94: 1834-1839, 1997[Abstract/Free Full Text].

215.   MATTER, K., M. BRAUCHBAR, K. BUCHER, AND H. P. HAURI. Sorting of endogenous plasma membrane proteins occurs from two sites in cultured human intestinal epithelial cells (Caco-2). Cell 60: 429-437, 1990[Medline].

216.   MATTER, K., K. BUCHER, AND H. P. HAURI. Microtubule perturbation retards both the direct and the indirect apical pathway but does not affect sorting of plasma membrane proteins in intestinal epithelial cells (Caco-2). EMBO J. 9: 3163-3170, 1990[Medline].

217.   MATTER, K., W. HUNZIKER, AND I. MELLMAN. Basolateral sorting of LDL receptor in MDCK cells: the cytoplasmic domain contains two tyrosine-dependent targeting determinants. Cell 71: 741-753, 1992[Medline].

218.   MATTER, K., AND I. MELLMAN. Mechanisms of cell polarity: sorting and transport in epithelial cells. Curr. Opin. Cell Biol. 6: 545-554, 1994[Medline].

219.   MATTER, K., J. A. WHITNEY, E. M. YAMAMOTO, AND I. MELLMAN. Common signals control low density lipoprotein receptor sorting in endosomes and the Golgi complex of MDCK cells. Cell 74: 1053-1064, 1993[Medline].

220.   MATTER, K., E. M. YAMAMOTO, AND I. MELLMAN. Structural requirements and sequence motifs for polarized sorting and endocytosis of LDL and Fc receptors in MDCK cells. J. Cell Biol. 126: 991-1004, 1994[Abstract/Free Full Text].

221.   MAYER, A., W. WICKNER, AND A. HAAS. Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell 85: 83-94, 1996[Medline].

222.   MAYOR, S., K. G. ROTHBERG, AND F. R. MAXFIELD. Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking. Science 264: 1948-1951, 1994[Abstract/Free Full Text].

223.   MAYS, R. W., K. A. BECK, AND W. J. NELSON. Organization and function of the cytoskeleton in polarized epithelial cells: a component of the protein sorting machinery. Curr. Opin. Cell Biol. 6: 16-24, 1994[Medline].

224.   MAYS, R. W., AND W. J. NELSON. Mechanisms for regulating the cell surface distribution of Na/K-ATPase in polarized epithelial cells. Chest 101, Suppl.: 50S-52S, 1992[Free Full Text].

225.   MAYS, R. W., K. A. SIEMERS, B. A. FRITZ, A. W. LOWE, G. VAN MEER, AND W. J. NELSON. Hierarchy of mechanisms involved in generating Na/K-ATPase polarity in MDCK epithelial cells. J. Cell Biol. 130: 1105-1115, 1995[Abstract/Free Full Text].

226.   MCCARTHY, K. M., I. B. SKARE, M. C. STANKEWICH, M. FURUSE, S. TSUKITA, R. A. ROGERS, R. D. LYNCH, AND E. E. SCHNEEBERGER. Occludin is a functional component of the tight junction. J. Cell Sci. 109: 2287-2298, 1996[Abstract].

227.   MCCREA, P. D., C. W. TURCK, AND B. GUMBINER. A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin. Science 254: 1359-1361, 1991[Abstract/Free Full Text].

228.   MCMAHON, H. T., Y. A. USHKARYOV, L. EDELMANN, E. LINK, T. BINZ, H. NIEMANN, R. JAHN, AND T. C. SUDHOF. Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature 364: 346-349, 1993[Medline].

229.   MCNEILL, H., M. OZAWA, R. KEMLER, AND W. J. NELSON. Novel function of the cell adhesion molecule uvomorulin as an inducer of cell surface polarity. Cell 62: 309-316, 1990[Medline].

230.   MCNEW, J. A., M. SOGAARD, N. M. LAMPEN, S. MACHIDA, R. R. YE, L. LACOMIS, P. TEMPST, J. E. ROTHMAN, AND T. H. SOLLNER. Ykt6p, a prenylated SNARE essential for endoplasmic reticulum-Golgi transport. J. Biol. Chem. 272: 17776-17783, 1997[Abstract/Free Full Text].

231.   MCQUEEN, N., D. P. NAYAK, E. B. STEPHENS, AND R. W. COMPANS. Polarized expression of a chimeric protein in which the transmembrane and cytoplasmic domains of the influenza virus hemagglutinin have been replaced by those of the vesicular stomatitis virus G protein. Proc. Natl. Acad. Sci. USA 83: 9318-9322, 1986[Abstract/Free Full Text].

232.   MEADS, T., AND T. A. SCHROER. Polarity and nucleation of microtubules in polarized epithelial cells. Cell. Motil. Cytoskeleton 32: 273-288, 1995[Medline].

233.   MIYAMOTO, S., S. K. AKIYAMA, AND K. M. YAMADA. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science 267: 883-885, 1995[Abstract/Free Full Text].

234.   MIYAMOTO, S., H. TERAMOTO, O. A. COSO, J. S. GUTKIND, P. D. BURBELO, S. K. AKIYAMA, AND K. M. YAMADA. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J. Cell Biol. 131: 791-805, 1995[Abstract/Free Full Text].

235.   MONLAUZEUR, L., A. RAJASEKARAN, M. CHAO, AND E. RODRIGUEZ. -BOULAN, AND A. LE BIVIC. A cytoplasmic tyrosine is essential for the basolateral localization of mutants of the human nerve growth factor receptor in Madin-Darby canine kidney cells. J. Biol. Chem. 270: 12219-12225, 1995[Abstract/Free Full Text].

236.   MOOSEKER, M. S.. Organization, chemistry, and assembly of the cytoskeletal apparatus of the intestinal brush border. Annu. Rev. Cell Biol. 1: 209-241, 1985.

237.   MOSTOV, K., G. APODACA, B. AROETI, AND C. OKAMOTO. Plasma membrane protein sorting in polarized epithelial cells. J. Cell Biol. 116: 577-583, 1992[Free Full Text].

238.   MOSTOV, K. E., P. BREITFELD, AND J. M. HARRIS. An anchor-minus form of the polymeric immunoglobulin receptor is secreted predominantly apically in Madin-Darby canine kidney cells. J. Cell Biol. 105: 2031-2036, 1987[Abstract/Free Full Text].

239.   MOSTOV, K. E., AND A. DE BRUYN. KOPS, AND D. L. DEITCHER. Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis. Cell 47: 359-364, 1986[Medline].

240.   MOSTOV, K. E., AND D. L. DEITCHER. Polymeric immunoglobulin receptor expressed in MDCK cells transcytoses IgA. Cell 46: 613-621, 1986[Medline].

241.   MURATA, M., J. PERANEN, R. SCHREINER, F. WIELAND, T. V. KURZCHALIA, AND K. SIMONS. VIP21/caveolin is a cholesterol-binding protein. Proc. Natl. Acad. Sci. USA 92: 10339-10343, 1995[Abstract/Free Full Text].

242.   MÜSCH, A., D. COHEN, AND E. RODRIGUEZ. -BOULAN. Myosin II is involved in the production of constitutive transport vesicles from the TGN. J. Cell Biol. 138: 291-306, 1997[Abstract/Free Full Text].

243.   MÜSCH, A., AND E. RODRIGUEZ. -BOULAN. Role of cytoplasmic motors in post-Golgi vesicular traffic. Soc. Gen. Physiol. Ser. 52: 55-67, 1997[Medline].

244.   MÜSCH, A., H. XU, D. SHIELDS, AND E. RODRIGUEZ. -BOULAN. Transport of vesicular stomatitis virus G protein to the cell surface is signal mediated in polarized and nonpolarized cells. J. Cell Biol. 133: 543-558, 1996[Abstract/Free Full Text].

245.   NAGAFUCHI, A., AND M. TAKEICHI. Cell binding function of E-cadherin is regulated by the cytoplasmic domain. EMBO J. 7: 3679-3684, 1988[Medline].

246.   NAGAFUCHI, A., AND M. TAKEICHI. Transmembrane control of cadherin-mediated cell adhesion: a 94 kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin. Cell. Regul. 1: 37-44, 1989[Medline].

247.   NAGAHAMA, M., L. ORCI, M. RAVAZZOLA, M. AMHERDT, L. LACOMIS, P. TEMPST, J. E. ROTHMAN, AND T. H. SOLLNER. A v-SNARE implicated in intra-Golgi transport. J. Cell Biol. 133: 507-516, 1996[Abstract/Free Full Text].

248.   NAIM, H. Y., D. T. DODDS, C. B. BREWER, AND M. G. ROTH. Apical and basolateral coated pits of MDCK cells differ in their rates of maturation into coated vesicles, but not in the ability to distinguish between mutant hemagglutinin proteins with different internalization signals. J. Cell Biol. 129: 1241-1250, 1995[Abstract/Free Full Text].

249.   NARULA, N., I. MCMORROW, G. PLOPPER, J. DOHERTY, K. S. MATLIN, B. BURKE, AND J. L. STOW. Identification of a 200-kD, brefeldin-sensitive protein on Golgi membranes. J. Cell Biol. 117: 27-38, 1992[Abstract/Free Full Text].

250.   NARULA, N., AND J. L. STOW. Distinct coated vesicles labeled for p200 bud from trans-Golgi network membranes. Proc. Natl. Acad. Sci. USA 92: 2874-2878, 1995[Abstract/Free Full Text].

251.   NELSON, W. J.. Cytoskeleton functions in membrane traffic in polarized epithelial cells. Semin. Cell Biol. 2: 375-385, 1991[Medline].

252.   NELSON, W. J., AND R. W. HAMMERTON. A membrane-cytoskeletal complex containing Na⁺,K⁺-ATPase, ankyrin, and fodrin in Madin-Darby canine kidney (MDCK) cells: implications for the biogenesis of epithelial cell polarity. J. Cell Biol. 108: 893-902, 1989[Abstract/Free Full Text].

253.   NELSON, W. J., E. M. SHORE, A. Z. WANG, AND R. W. HAMMERTON. Identification of a membrane-cytoskeletal complex containing the cell adhesion molecule uvomorulin (E-cadherin), ankyrin, and fodrin in Madin-Darby canine kidney epithelial cells. J. Cell Biol. 110: 349-357, 1990[Abstract/Free Full Text].

254.   NELSON, W. J., AND P. J. VESHNOCK. Dynamics of membrane-skeleton (fodrin) organization during development of polarity in Madin-Darby canine kidney epithelial cells. J. Cell Biol. 103: 1751-1765, 1986[Abstract/Free Full Text].

255.   NELSON, W. J., AND P. J. VESHNOCK. Ankyrin binding to (Na⁺ + K⁺)ATPase and implications for the organization of membrane domains in polarized cells. Nature 328: 533-536, 1987[Medline].

256.   NICHOLS, B. J., C. UNGERMANN, H. R. PELHAM, W. T. WICKNER, AND A. HAAS. Homotypic vacuolar fusion mediated by t- and v-SNAREs. Nature 387: 199-202, 1997[Medline].

257.   NIELSEN, S., D. MARPLES, H. BIRN, M. MOHTASHAMI, N. O. DALBY, M. TRIMBLE, AND M. KNEPPER. Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. Colocalization with Aquaporin-2 water channels. J. Clin. Invest. 96: 1834-1844, 1995.

258.   NIESET, J. E., A. R. REDFIELD, F. JIN, K. A. KNUDSEN, K. R. JOHNSON, AND M. J. WHEELOCK. Characterization of the interactions of alpha-catenin with alpha-actinin and beta-catenin/plakoglobin. J. Cell Sci. 110: 1013-1022, 1997[Abstract].

259.   NOJIMA, Y., N. MORINO, T. MIMURA, K. HAMASAKI, H. FURUYA, R. SAKAI, T. SATO, K. TACHIBANA, C. MORIMOTO, Y. YAZAKI, AND E. AL. Integrin-mediated cell adhesion promotes tyrosine phosphorylation of p130Cas, a Src homology 3-containing molecule having multiple Src homology 2-binding motifs. J. Biol. Chem. 270: 15398-15402, 1995[Abstract/Free Full Text].

260.   NOVICK, P., AND P. BRENNWALD. Friends and family: the role of the Rab GTPases in vesicular traffic. Cell 75: 597-601, 1993[Medline].

261.   ODORIZZI, G., AND I. S. TROWBRIDGE. Structural requirements for basolateral sorting of the human transferrin receptor in the biosynthetic and endocytic pathways of Madin-Darby canine kidney cells. J. Cell Biol. 137: 1255-1264, 1997[Abstract/Free Full Text].

262.   ODORIZZI, G., AND I. S. TROWBRIDGE. Structural requirements for major histocompatibility complex class II invariant chain trafficking in polarized Madin-Darby canine kidney cells. J. Biol. Chem. 272: 11757-11762, 1997[Abstract/Free Full Text].

263.   OHNO, H., M. C. FOURNIER, G. POY, AND J. S. BONIFACINO. Structural determinants of interaction of tyrosine-based sorting signals with the adaptor medium chains. J. Biol. Chem. 271: 29009-29015, 1996[Abstract/Free Full Text].

264.   OHNO, H., J. STEWART, M. C. FOURNIER, H. BOSSHART, I. RHEE, S. MIYATAKE, T. SAITO, A. GALLUSSER, T. KIRCHHAUSEN, AND J. S. BONIFACINO. Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269: 1872-1875, 1995[Abstract/Free Full Text].

265.   OJAKIAN, G. K., W. J. NELSON, AND K. A. BECK. Mechanisms for de novo biogenesis of an apical membrane compartment in groups of simple epithelial cells surrounded by extracellular matrix. J. Cell Sci. 110: 2781-2794, 1997[Abstract].

266.   OJAKIAN, G. K., AND R. SCHWIMMER. The polarized distribution of an apical cell surface glycoprotein is maintained by interactions with the cytoskeleton of Madin-Darby canine kidney cells. J. Cell Biol. 107: 2377-2387, 1988[Abstract/Free Full Text].

267.   OJAKIAN, G. K., AND R. SCHWIMMER. Antimicrotubule drugs inhibit the polarized insertion of an intracellular glycoprotein pool into the apical membrane of Madin-Darby canine kidney (MDCK) cells. J. Cell Sci. 103: 677-687, 1992[Abstract].

268.   OJAKIAN, G. K., AND R. SCHWIMMER. Regulation of epithelial cell surface polarity reversal by beta 1 integrins. J. Cell Sci. 107: 561-576, 1994[Abstract].

269.   OKAMOTO, M., AND T. C. SUDHOF. Mints, Munc18-interacting proteins in synaptic vesicle exocytosis. J. Biol. Chem. 272: 31459-31464, 1997[Abstract/Free Full Text].

270.   OOI, C. E., J. E. MOREIRA, E. C. DELL'ANGELICA, G. POY, D. A. WASSARMAN, AND J. S. BONIFACINO. Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila eye color mutant garnet. EMBO J. 16: 4508-4518, 1997[Medline].

271.   OTEY, C. A., F. M. PAVALKO, AND K. BURRIDGE. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J. Cell Biol. 111: 721-729, 1990[Abstract/Free Full Text].

272.   OTEY, C. A., G. B. VASQUEZ, K. BURRIDGE, AND B. W. ERICKSON. Mapping of the alpha-actinin binding site within the beta 1 integrin cytoplasmic domain. J. Biol. Chem. 268: 21193-21197, 1993[Abstract/Free Full Text].

273.   OZAWA, M., H. BARIBAULT, AND R. KEMLER. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J. 8: 1711-1717, 1989[Medline].

274.   PAEK, I., L. ORCI, M. RAVAZZOLA, B. H. ERDJUMENT, M. AMHERDT, P. TEMPST, T. H. SOLLNER, AND J. E. ROTHMAN. ERS-24, a mammalian v-SNARE implicated in vesicle traffic between the ER and the Golgi. J. Cell Biol. 137: 1017-1028, 1997[Abstract/Free Full Text].

275.   PARCZYK, K., W. HAASE, AND K. C. KONDOR. Microtubules are involved in the secretion of proteins at the apical cell surface of the polarized epithelial cell, Madin-Darby canine kidney. J. Biol. Chem. 264: 16837-16846, 1989[Abstract/Free Full Text].

276.   PARSONS, J. T.. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr. Opin. Cell Biol. 8: 146-152, 1996[Medline].

277.   PARTON, R. G.. Caveolae and caveolins. Curr. Opin. Cell Biol. 8: 542-548, 1996[Medline].

278.   PASDAR, M., AND W. J. NELSON. Regulation of desmosome assembly in epithelial cells: kinetics of synthesis, transport, and stabilization of desmoglein I, a major protein of the membrane core domain. J. Cell Biol. 109: 163-177, 1989[Abstract/Free Full Text].

279.   PAVALKO, F. M., AND K. BURRIDGE. Disruption of the actin cytoskeleton after microinjection of proteolytic fragments of alpha-actinin. J. Cell Biol. 114: 481-491, 1991[Abstract/Free Full Text].

280.   PAVELKA, M., AND A. ELLINGER. Effect of colchicine on the Golgi complex of rat pancreatic acinar cells. J. Cell Biol. 97: 737-748, 1983[Abstract/Free Full Text].

281.   PEARL, M., D. FISHKIND, M. MOOSEKER, D. KEENE, AND T. KELLER III. Studies on the spectrin-like protein from the intestinal brush border, TW 260/240, and characterization of its interaction with the cytoskeleton and actin. J. Cell Biol. 98: 66-78, 1984.

282.   PENG, X. R., X. YAO, D. C. CHOW, J. G. FORTE, AND M. K. BENNETT. Association of syntaxin 3 and vesicle-associated membrane protein (VAMP) with H⁺/K⁺-ATPase-containing tubulovesicles in gastric parietal cells. Mol. Biol. Cell 8: 399-407, 1997[Abstract].

283.   PETCH, L. A., S. M. BOCKHOLT, A. BOUTON, J. T. PARSONS, AND K. BURRIDGE. Adhesion-induced tyrosine phosphorylation of the p130 src substrate. J. Cell Sci. 108: 1371-1379, 1995[Abstract].

284.   PETERS, C., M. BRAUN, B. WEBER, M. WENLAND, B. SCHMIDT, R. POHLMANN, A. WAHEED, AND K. VON FIGURA. Targeting of a lysosomal membrane protein: a tyrosine-containing endocytosis signal in the cytoplasmic tail of lysosomal acid phosphatase is necessary and sufficient for targeting to lysosomes. EMBO J. 9: 3497-3506, 1990[Medline].

285.   PEVSNER, J., S. C. HSU, J. E. BRAUN, N. CALAKOS, A. E. TING, M. K. BENNETT, AND R. H. SCHELLER. Specificity and regulation of a synaptic vesicle docking complex. Neuron 13: 353-361, 1994[Medline].

286.   PEVSNER, J., S. C. HSU, AND R. H. SCHELLER. n-Sec1: a neural-specific syntaxin-binding protein. Proc. Natl. Acad. Sci. USA 91: 1445-1449, 1994[Abstract/Free Full Text].

287.   PINSON, K. I., L. DUNBAR, L. SAMUELSON, AND D. L. GUMUCIO. Targeted disruption of the mouse villin gene does not impair the morphogenesis of microvilli. Dev. Dyn. 211: 109-121, 1998[Medline].

288.   POWELL, S. K., M. P. LISANTI, AND E. J. RODRIGUEZ. -BOULAN. Thy-1 expresses two signals for apical localization in epithelial cells. Am. J. Physiol. 260(Cell Physiol. 29): C715-C720, 1991[Abstract/Free Full Text].

289.   PRILL, V., L. LEHMANN, F. K. VON, AND C. PETERS. The cytoplasmic tail of lysosomal acid phosphatase contains overlapping but distinct signals for basolateral sorting and rapid internalization in polarized MDCK cells. EMBO J. 12: 2181-2193, 1993[Medline].

290.   RAGNO, P., A. ESTREICHER, A. GOS, A. WOHLWEND, D. BELIN, AND J. D. VASSALLI. Polarized secretion of urokinase-type plasminogen activator by epithelial cells. Exp. Cell Res. 203: 236-243, 1992[Medline].

291.   RAPOPORT, I., Y. C. CHEN, P. CUPERS, S. E. SHOELSON, AND T. KIRCHHAUSEN. Dileucine-based sorting signals bind to the  chain of AP-1 at a site distinct and regulated differently from the tyrosine-based motif-binding site. EMBO J. 17: 2148-2155, 1998[Medline].

292.   RESZKA, A. A., Y. HAYASHI, AND A. F. HORWITZ. Identification of amino acid sequences in the integrin beta 1 cytoplasmic domain implicated in cytoskeletal association. J. Cell Biol. 117: 1321-1330, 1992[Abstract/Free Full Text].

293.   RIENTO, K., J. JANTTI, S. JANSSON, S. HIELM, E. LEHTONEN, C. EHNHOLM, S. KERANEN, AND V. M. OLKKONEN. A sec1-related vesicle-transport protein that is expressed predominantly in epithelial cells. Eur. J. Biochem. 239: 638-646, 1996[Medline].

294.   RIMM, D. L., E. R. KOSLOV, P. KEBRIAEI, C. D. CIANCI, AND J. S. MORROW. Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc. Natl. Acad. Sci. USA 92: 8813-8817, 1995[Abstract/Free Full Text].

295.   RINDLER, M. J., I. E. IVANOV, AND D. D. SABATINI. Microtubule-acting drugs lead to the nonpolarized delivery of the influenza hemagglutinin to the cell surface of polarized Madin-Darby canine kidney cells. J. Cell Biol. 104: 231-241, 1987[Abstract/Free Full Text].

296.   RODIONOV, D. G., AND O. BAKKE. Medium chains of adaptor complexes AP-1 and AP-2 recognize leucine-based sorting signals from the invariant chain. J. Biol. Chem. 273: 6005-6008, 1998[Abstract/Free Full Text].

297.   RODMAN, J. S., M. MOOSEKER, AND M. G. FARQUHAR. Cytoskeletal proteins of the rat kidney proximal tubule brush border. Eur. J. Cell Biol. 42: 319-327, 1986[Medline].

298.   RODRIGUEZ-BOULAN, E., AND W. J. NELSON. Morphogenesis of the polarized epithelial cell phenotype. Science 245: 718-725, 1989.

299.   RODRIGUEZ-BOULAN, E., K. T. PASKIET, AND D. D. SABATINI. Assembly of enveloped viruses in Madin-Darby canine kidney cells: polarized budding from single attached cells and from clusters of cells in suspension. J. Cell Biol. 96: 866-874, 1983.

300.   RODRIGUEZ-BOULAN, E., AND M. PENDERGAST. Polarized distribution of viral envelope proteins in the plasma membrane of infected epithelial cells. Cell 20: 45-54, 1980.

301.   RODRIGUEZ-BOULAN, E., AND S. K. POWELL. Polarity of epithelial and neuronal cells. Annu. Rev. Cell Biol. 8: 395-427, 1992.

302.   RODRIGUEZ-BOULAN, E., AND D. D. SABATINI. Asymmetric budding of viruses in epithelial monlayers: a model system for study of epithelial polarity. Proc. Natl. Acad. Sci. USA 75: 5071-5075, 1978.

303.   ROHRER, J., A. SCHWEIZER, D. RUSSELL, AND S. KORNFELD. The targeting of Lamp1 to lysosomes is dependent on the spacing of its cytoplasmic tail tyrosine sorting motif relative to the membrane. J. Cell Biol. 132: 565-576, 1996[Abstract/Free Full Text].

304.   ROTH, M. G., J. P. FITZPATRICK, AND R. W. COMPANS. Polarity of influenza and vesicular stomatitis virus maturation in MDCK cells: lack of a requirement for glycosylation of viral glycoproteins. Proc. Natl. Acad. Sci. USA 76: 6430-6434, 1979[Abstract/Free Full Text].

305.   ROTH, M. G., D. GUNDERSEN, N. PATIL, AND E. RODRIGUEZ. -BOULAN. The large external domain is sufficient for the correct sorting of secreted or chimeric influenza virus hemagglutinins in polarized monkey kidney cells. J. Cell Biol. 104: 769-782, 1987[Abstract/Free Full Text].

306.   ROTHBERG, K. G., J. K. HEUSER, W. C. DONZELL, Y.-S. YING, J. R. GLENNEY, AND R. G. W. ANDERSON. Caveolin, a protein component of caveolae membrane coats. Cell 68: 673-682, 1990.

307.   ROTHMAN, J. E., AND T. H. SOLLNER. Throttles and dampers: controlling the engine of membrane fusion. Science 276: 1212-1213, 1997[Free Full Text].

308.   ROTHMAN, J. E., AND G. WARREN. Implications of the SNARE hypothesis for intracellular membrane topology and dynamics. Curr. Biol. 4: 220-233, 1994[Medline].

309.   SAELMAN, E. U. M., P. J. KEELY, AND S. A. SANTORO. Loss of MDCK cell ₂₁ integrin expression results in reduced cyst formation, failure of hepatocyte growth factor/scatter factor-induced branching morphogenesis, and increased apoptosis. J. Cell Sci. 108: 3531-3540, 1995[Abstract].

310.   SAITOU, M., K. FUJIMOTO, Y. DOI, M. ITOH, T. FUJIMOTO, M. FURUSE, H. TAKANO, T. NODA, AND S. TSUKITA. Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J. Cell Biol. 141: 397-408, 1998[Abstract/Free Full Text].

311.   SALAS, P. J., D. E. MISEK, AND D. E. VEGA. -SALAS, D. GUNDERSEN, M. CEREIJIDO, AND E. RODRIGUEZ-BOULAN. Microtubules and actin filaments are not critically involved in the biogenesis of epithelial cell surface polarity. J. Cell Biol. 102: 1853-1867, 1986[Abstract/Free Full Text].

312.   SALMINEN, A., AND P. J. NOVICK. A ras-like protein is required for a post-Golgi event in yeast secretion. Cell 49: 527-538, 1987[Medline].

313.   SARGIACOMO, M., M. SUDOL, Z. TANG, AND M. P. LISANTI. Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J. Cell Biol. 122: 789-807, 1993[Abstract/Free Full Text].

314.   SAUCAN, L., AND G. E. PALADE. Differential colchicine effects on the transport of membrane and secretory proteins in rat hepatocytes in vivo: bipolar secretion of albumin. Hepatology 15: 714-721, 1992[Medline].

315.   SCHALLER, M. D., C. A. BORGMAN, B. S. COBB, R. R. VINES, A. B. REYNOLDS, AND J. T. PARSONS. pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl. Acad. Sci. USA 89: 5192-5196, 1992[Abstract/Free Full Text].

316.   SCHEIFFELE, P., J. PERANEN, AND K. SIMONS. N-glycans as apical sorting signals in epithelial cells. Nature 378: 96-98, 1995[Medline].

317.   SCHEIFFELE, P., M. G. ROTH, AND K. SIMONS. Interaction of influenza virus haemagglutinin with sphingolipid-cholesterol membrane domains via its transmembrane domain. EMBO J. 16: 5501-5508, 1997[Medline].

318.   SCHEIFFELE, P., P. VERKADE, A. M. FRA, H. VIRTA, K. SIMONS, AND E. IKONEN. Caveolin-1 and -2 in the exocytic pathway of MDCK cells. J. Cell Biol. 140: 795-806, 1998[Abstract/Free Full Text].

319.   SCHEKMAN, R., AND L. ORCI. Coat proteins and vesicle budding. Science 271: 1526-1533, 1996[Abstract].

320.   SCHOENENBERGER, C. A., A. ZUK, G. M. ZINKL, D. KENDALL, AND K. S. MATLIN. Integrin expression and localization in normal MDCK cells and transformed MDCK cells lacking apical polarity. J. Cell Sci. 107: 527-541, 1994[Abstract].

321.   SCHU, P. V., K. TAKEGAWA, M. J. FRY, J. H. STACK, M. D. WATERFIELD, AND S. D. EMR. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260: 88-91, 1993[Abstract/Free Full Text].

322.   SCHWIMMER, R., AND G. K. OJAKIAN. The alpha 2 beta 1 integrin regulates collagen-mediated MDCK epithelial membrane remodeling and tubule formation. J. Cell Sci. 108: 2487-2498, 1995[Abstract].

323.   SHIBAMOTO, S., M. HAYAKAWA, K. TAKEUCHI, T. HORI, K. MIYAZAWA, N. KITAMURA, K. R. JOHNSON, M. J. WHEELOCK, N. MATSUYOSHI, M. TAKEICHI, AND F. ITO. Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes. J. Cell Biol. 128: 949-957, 1995[Abstract/Free Full Text].

324.   SIMON, J. P., T. H. SHEN, I. E. IVANOV, D. GRAVOTTA, T. MORIMOTO, M. ADESNIK, AND D. D. SABATINI. Coatamer, but not P200/myosin II, is required for the in vitro formation of trans-Golgi network-derived vesicles containing the envelope glycoprotein of vesicular stomatitis virus. Proc. Natl. Acad. Sci. USA 95: 1073-1078, 1998[Abstract/Free Full Text].

325.   SIMONS, K., AND E. IKONEN. Functional rafts in cell membranes. Nature 387: 569-572, 1997[Medline].

326.   SIMONS, K., AND G. VAN MEER. Lipid sorting in epithelial cells. Biochemistry 27: 6197-6202, 1988[Medline].

327.   SIMONS, K., AND A. WANDINGER. -NESS. Polarized sorting in epithelia. Cell 62: 207-210, 1990[Medline].

328.   SIMONSEN, A., E. STANG, B. BREMNES, M. ROE, K. PRYDZ, AND O. BAKKE. Sorting of MHC class II molecules and the associated invariant chain (Ii) in polarized MDCK cells. J. Cell Sci.: 110: 597-609, 1997.

329.   SIMPSON, F., N. A. BRIGHT, M. A. WEST, L. S. NEWMAN, R. B. DARNELL, AND M. S. ROBINSON. A novel adaptor-related protein complex. J. Cell Biol. 133: 749-760, 1996[Abstract/Free Full Text].

330.   SIMPSON, F., A. A. PEDEN, L. CHRISTOPOULOU, AND M. S. ROBINSON. Characterization of the adaptor-related protein complex, AP-3. J. Cell Biol. 137: 835-845, 1997[Abstract/Free Full Text].

331.   SOGAARD, M., K. TANI, R. R. YE, S. GEROMANOS, P. TEMPST, T. KIRCHHAUSEN, J. E. ROTHMAN, AND T. SÖLLNER. A rab protein is required for the assembly of SNARE complexes in the docking of transport vesicles. Cell 78: 937-948, 1994[Medline].

332.   SOLLNER, T., M. K. BENNETT, S. W. WHITEHEART, R. H. SCHELLER, AND J. E. ROTHMAN. A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75: 409-418, 1993[Medline].

333.   SOLLNER, T., S. W. WHITEHEART, M. BRUNNER, AND H. ERDJUMENT. -BROMAGE, S. GEROMANOS, P. TEMPST, AND J. E. ROTHMAN. SNAP receptors implicated in vesicle targeting and fusion. Nature 362: 318-324, 1993[Medline].

334.   STADDON, J. M., C. SMALES, C. SCHULZE, F. S. ESCH, AND L. L. RUBIN. p120, a p120-related protein (p100), and the cadherin/catenin complex. J. Cell Biol. 130: 369-381, 1995[Abstract/Free Full Text].

335.   STEVENSON, B. R., J. M. ANDERSON, D. A. GOODENOUGH, AND M. S. MOOSEKER. Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance. J. Cell Biol. 107: 2401-2408, 1988[Abstract/Free Full Text].

336.   STOORVOGEL, W., V. OORSCHOT, AND H. J. GEUZE. A novel class of clathrin-coated vesicles budding from endosomes. J. Cell Biol. 132: 21-33, 1996[Abstract/Free Full Text].

337.   STOSSEL, T. P.. On the crawling of animal cells. Science 260: 1086-1094, 1993[Abstract/Free Full Text].

338.   SUDHOF, T. C., M. BAUMERT, M. S. PERIN, AND R. JAHN. A synaptic vesicle membrane protein is conserved from mammals to Drosophila. Neuron 2: 1475-1481, 1989[Medline].

339.   TAKEI, K., P. S. MCPHERSON, S. L. SCHMID, AND P. DE CAMILLI. Tubular membrane invaginations coated by dynamin rings are induced by GTP-gamma-S in nerve terminals. Nature 374: 186-190, 1995[Medline].

340.   TAKITO, J., C. HIKITA, AND Q. AL. -AWQATI. Hensin, a new collecting duct protein involved in the in vitro plasticity of intercalated cell polarity. J. Clin. Invest. 98: 2324-2331, 1996[Medline].

341.   TELLAM, J. T., S. L. MACAULAY, S. MCINTOSH, D. R. HEWISH, C. W. WARD, AND D. E. JAMES. Characterization of Munc-18c and syntaxin-4 in 3T3-L1 adipocytes. Putative role in insulin-dependent movement of GLUT-4. J. Biol. Chem. 272: 6179-6186, 1997[Abstract/Free Full Text].

342.   TELLAM, J. T., S. MCINTOSH, AND D. E. JAMES. Molecular identification of two novel Munc-18 isoforms expressed in non-neuronal tissues. J. Biol. Chem. 270: 5857-5863, 1995[Abstract/Free Full Text].

343.   TERBUSH, D. R., T. MAURICE, D. ROTH, AND P. NOVICK. The Exocyst is a multiprotein complex required for exocytosis in Saccharomyces cerevisiae. EMBO J. 15: 6483-6494, 1996[Medline].

344.   TERBUSH, D. R., AND P. NOVICK. Sec6, Sec8, and Sec15 are components of a multisubunit complex which localizes to small bud tips in Saccharomyces cerevisiae. J. Cell Biol. 130: 299-312, 1995[Abstract/Free Full Text].

345.   THOMAS, D. C., C. B. BREWER, AND M. G. ROTH. Vesicular stomatitis virus glycoprotein contains a dominant cytoplasmic basolateral sorting signal critically dependent upon a tyrosine. J. Biol. Chem. 268: 3313-3320, 1993[Abstract/Free Full Text].

346.   THOMAS, D. C., AND M. G. ROTH. The basolateral targeting signal in the cytoplasmic domain of glycoprotein G from vesicular stomatitis virus resembles a variety of intracellular targeting motifs related by primary sequence but having diverse targeting activities. J. Biol. Chem. 269: 15732-15739, 1994[Abstract/Free Full Text].

347.   THYBERG, J., AND S. MOSKALEWSKI. Microtubules and the organization of the Golgi complex. Exp. Cell Res. 159: 1-16, 1985[Medline].

348.   TING, A. E., C. D. HAZUKA, S. C. HSU, M. D. KIRK, A. J. BEAN, AND R. H. SCHELLER. rSec6 and rSec8, mammalian homologs of yeast proteins essential for secretion. Proc. Natl. Acad. Sci. USA 92: 9613-9617, 1995[Abstract/Free Full Text].

349.   TRIMBLE, W. S., D. M. COWAN, AND R. H. SCHELLER. VAMP-1: a synaptic vesicle-associated integral membrane protein. Proc. Natl. Acad. Sci. USA 85: 4538-4542, 1988[Abstract/Free Full Text].

350.   TROWBRIDGE, I. S., J. F. COLLAWN, AND C. R. HOPKINS. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu. Rev. Cell Biol. 9: 129-161, 1993.

351.   TSUKITA, S., K. OISHI, T. AKIYAMA, Y. YAMANASHI, T. YAMAMOTO, AND S. TSUKITA. Specific proto-oncogene tyrosine kinases of src family are enriched in cell-to-cell junctions where the level of tyrosine phosphorylation is elevated. J. Cell Biol. 113: 867-879, 1991[Abstract/Free Full Text].

352.   TURNER, C. E., J. R. GLENNEY, AND K. BURRIDGE. Paxillin: a new vinculin-binding protein present in focal adhesions. J. Cell Biol. 111: 1059-1068, 1990[Abstract/Free Full Text].

353.   TURNER, J. R., AND A. M. TARTAKOFF. The response of the Golgi complex to microtubule alterations: the roles of metabolic energy and membrane traffic in Golgi complex organization. J. Cell Biol. 109: 2081-2088, 1989[Abstract/Free Full Text].

354.   ULLRICH, O., K. MANN, W. HAASE, AND B. C. KOCH. Biosynthesis and secretion of an osteopontin-related 20-kDa polypeptide in the Madin-Darby canine kidney cell line. J. Biol. Chem. 266: 3518-3525, 1991[Abstract/Free Full Text].

355.   UNGERMANN, C., B. J. NICHOLS, H. R. PELHAM, AND W. WICKNER. A vacuolar v-t-SNARE complex, the predominant form in vivo and on isolated vacuoles, is disassembled and activated for docking and fusion. J. Cell Biol. 140: 61-69, 1998[Abstract/Free Full Text].

356.   URBAN, J., K. PARCZYK, A. LEUTZ, M. KAYNE, AND C. KONDOR. -KOCH. Constitutive apical secretion of an 80-kD sulfated glycoprotein complex in the polarized epithelial Madin-Darby canine kidney cell line. J. Cell Biol. 105: 2735-2743, 1987[Abstract/Free Full Text].

357.   VAN ADELSBERG, J., J. C. EDWARDS, J. TAKITO, B. KISS, AND Q. AL. -AWQATI. An induced extracellular matrix protein reverses the polarity of band 3 in intercalated epithelial cells. Cell 76: 1053-1061, 1994[Medline].

358.   VAN DER SLUIJS, P., M. K. BENNETT, C. ANTONY, K. SIMONS, AND T. E. KREIS. Binding of exocytic vesicles from MDCK cells to microtubules in vitro. J. Cell Sci. 95: 545-553, 1990[Abstract/Free Full Text].

359.   VAN ITALLIE, C. M., AND J. M. ANDERSON. Occludin confers adhesiveness when expressed in fibroblasts. J. Cell Sci. 110: 1113-1121, 1997[Abstract].

360.   VAN MEER, G., B. GUMBINER, AND K. SIMONS. The tight junction does not allow lipid molecules to diffuse from one epithelial cell to the next. Nature 322: 639-641, 1986[Medline].

361.   VAN MEER, G., AND K. SIMONS. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J. 5: 1455-1464, 1986[Medline].

362.   VAN ZEIJL, M. J., AND K. S. MATLIN. Microtubule perturbation inhibits intracellular transport of an apical membrane glycoprotein in a substrate-dependent manner in polarized Madin-Darby canine kidney epithelial cells. Cell Regul. 1: 921-936, 1990[Medline].

363.   VEGA-SALAS, D. E., P. J. SALAS, D. GUNDERSEN, AND E. RODRIGUEZ-BOULAN. Formation of the apical pole of epithelial (Madin-Darby canine kidney) cells: polarity of an apical protein is independent of tight junctions while segregation of a basolateral marker requires cell-cell interactions. J. Cell Biol. 104: 905-916, 1987.

364.   VEGA-SALAS, D. E., P. J. SALAS, AND E. RODRIGUEZ-BOULAN. Modulation of the expression of an apical plasma membrane protein of Madin-Darby canine kidney epithelial cells: cell-cell interactions control the appearance of a novel intracellular storage compartment. J. Cell Biol. 104: 1249-1259, 1987.

365.   VEGA-SALAS, D. E., P. J. SALAS, AND E. RODRIGUEZ-BOULAN. Exocytosis of vacuolar apical compartment (VAC): a cell-cell contact controlled mechanism for the establishment of the apical plasma membrane domain in epithelial cells. J. Cell Biol. 107: 1717-1728, 1988.

366.   VEIT, M., T. H. SOLLNER, AND J. E. ROTHMAN. Multiple palmitoylation of synaptotagmin and the t-SNARE SNAP-25. FEBS Lett. 385: 119-123, 1996[Medline].

367.   VERHAGE, M., K. J. DE VRIES, H. ROSHOL, J. P. BURBACH, W. H. GISPEN, AND T. C. SUDHOF. DOC2 proteins in rat brain: complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion. Neuron 18: 453-461, 1997[Medline].

368.   VOGEL, L. K., M. SPIESS, H. SJOSTROM, AND O. NOREN. Evidence for an apical sorting signal on the ectodomain of human aminopeptidase N. J. Biol. Chem. 267: 2794-2797, 1992[Abstract/Free Full Text].

369.   WACHSSTOCK, D. H., J. A. WILKINS, AND S. LIN. Specific interaction of vinculin with alpha-actinin. Biochem. Biophys. Res. Commun. 146: 554-560, 1987[Medline].

370.   WALCH-SOLIMENA, C., J. BLASI, L. EDELMANN, E. R. CHAPMAN, G. FISCHER VON MOLLARD, AND R. JAHN. The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling. J. Cell Biol. 128: 637-645, 1995.

371.   WANG, A. Z., G. K. OJAKIAN, AND W. J. NELSON. Steps in the morphogenesis of a polarized epithelium. I. Uncoupling the roles of cell-cell and cell-substratum contact in establishing plasma membrane polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95: 137-151, 1990[Abstract/Free Full Text].

372.   WANG, A. Z., G. K. OJAKIAN, AND W. J. NELSON. Steps in the morphogenesis of a polarized epithelium. II. Disassembly and assembly of plasma membrane domains during reversal of epithelial cell polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95: 153-165, 1990[Abstract/Free Full Text].

373.   WANG, A. Z., J. C. WANG, G. K. OJAKIAN, AND W. J. NELSON. Determinants of apical membrane formation and distribution in multicellular epithelial MDCK cysts. Am. J. Physiol. 267(Cell Physiol. 36): C473-C481, 1994[Abstract/Free Full Text].

374.   WEBER, E., G. BERTA, A. TOUSSON, P. ST. JOHN, M. W. GREEN, U. GOPALOKRISHNAN, T. JILLING, E. J. SORSCHER, T. S. ELTON, D. R. ABRAHAMSON, AND K. L. KIRK. Expression and polarized targeting of a rab3 isoform in epithelial cells. J. Cell Biol. 125: 583-594, 1994[Abstract/Free Full Text].

375.   WEIDMAN, P. J., P. MELANCON, M. R. BLOCK, AND J. E. ROTHMAN. Binding of an N-ethylmaleimide-sensitive fusion protein to Golgi membranes requires both a soluble protein(s) and an integral membrane receptor. J. Cell Biol. 108: 1589-1596, 1989[Abstract/Free Full Text].

376.   WEIMBS, T., S. H. LOW, S. J. CHAPIN, AND K. E. MOSTOV. Apical targeting in polarized epithelial cells: there's more afloat than rafts. Trends Cell Biol. 7: 393-399, 1997.[Medline]

377.   WEIMBS, T., S. H. LOW, S. J. CHAPIN, K. E. MOSTOV, P. BUCHER, AND K. HOFMANN. A conserved domain is present in different families of vesicular fusion proteins: a new superfamily. Proc. Natl. Acad. Sci. USA 94: 3046-3051, 1997[Abstract/Free Full Text].

378.   WEISZ, O. A., C. E. MACHAMER, AND A. L. HUBBARD. Rat liver dipeptidylpeptidase IV contains competing apical and basolateral targeting information. J. Biol. Chem. 267: 22282-22288, 1992[Abstract/Free Full Text].

379.   WHITEHEART, S. W., M. BRUNNER, D. W. WILSON, M. WIEDMANN, AND J. E. ROTHMAN. Soluble N-ethylmaleimide-sensitive fusion attachment proteins (SNAPs) bind to a multi-SNAP receptor complex in Golgi membranes. J. Biol. Chem. 267: 12239-12243, 1992[Abstract/Free Full Text].

380.   WILLOTT, E., M. S. BALDA, A. S. FANNING, B. JAMESON, I. C. VAN, AND J. M. ANDERSON. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc. Natl. Acad. Sci. USA 90: 7834-7838, 1993[Abstract/Free Full Text].

381.   WILSON, D. W., S. W. WHITEHEART, M. WIEDMANN, M. BRUNNER, AND J. E. ROTHMAN. A multisubunit particle implicated in membrane fusion. J. Cell Biol. 117: 531-538, 1992[Abstract/Free Full Text].

382.   WILSON, J. M., N. FASEL, AND J. P. KRAEHENBUHL. Polarity of endogenous and exogenous glycosyl-phosphatidylinositol-anchored membrane proteins in Madin-Darby canine kidney cells. J. Cell Sci. 96: 143-149, 1990[Abstract/Free Full Text].

383.   WOLLNER, D. A., K. A. KRZEMINSKI, AND W. J. NELSON. Remodeling the cell surface distribution of membrane proteins during the development of epithelial cell polarity. J. Cell Biol. 116: 889-899, 1992[Abstract/Free Full Text].

384.   WONG, V.. Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am. J. Physiol. 273(Cell Physiol. 42): C1859-C1867, 1997[Abstract/Free Full Text].

385.   WOZNIAK, M., J. R. KEEFER, C. SAUNDERS, AND L. E. LIMBIRD. Differential targeting and retention of G protein-coupled receptors in polarized epithelial cells. J. Recept. Signal Transduct. Res. 17: 373-383, 1997[Medline].

386.   XING, Z., H. C. CHEN, J. K. NOWLEN, S. J. TAYLOR, D. SHALLOWAY, AND J. L. GUAN. Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol. Biol. Cell 5: 413-421, 1994[Abstract].

387.   YAMADA, K. M., AND S. MIYAMOTO. Integrin transmembrane signaling and cytoskeletal control. Curr. Opin. Cell Biol. 7: 681-689, 1995[Medline].

388.   YEAMAN, C., M. HEINFLINK, AND E. FALCK. -PEDERSEN, E. RODRIGUEZ-BOULAN, AND M. C. GERSHENGORN. Polarity of TRH receptors in transfected MDCK cells is independent of endocytosis signals and G protein coupling. Am. J. Physiol 271(Cell Physiol. 40): C753-C762, 1996[Abstract/Free Full Text].

389.   YEAMAN, C., A. H. LE GALL, A. N. BALDWIN, L. MONLAUZEUR, A. LE BIVIC, AND E. RODRIGUEZ. -BOULAN. The O-glycosylated stalk domain is required for apical sorting of neurotrophin receptors in polarized MDCK cells. J. Cell Biol. 139: 929-940, 1997[Abstract/Free Full Text].

390.   YOSHIMORI, T., P. KELLER, M. G. ROTH, AND K. SIMONS. Different biosynthetic transport routes to the plasma membrane in BHK and CHO cells. J. Cell Biol. 133: 247-256, 1996[Abstract/Free Full Text].

391.   ZAHRAOUI, A., G. JOBERTY, M. ARPIN, J. J. FONTAINE, R. HELLIO, A. TAVITIAN, AND D. LOUVARD. A small rab GTPase is distributed in cytoplasmic vesicles in nonpolarized cells but colocalizes with the tight junction marker ZO-1 in polarized epithelial cells. J. Cell Biol. 124: 101-115, 1994[Abstract/Free Full Text].

392.   ZUK, A., AND K. S. MATLIN. Apical beta 1 integrin in polarized MDCK cells mediates tubulocyst formation in response to type I collagen overlay. J. Cell Sci. 109: 1875-1889, 1996[Abstract].

393.   ZURZOLO, C., M. P. LISANTI, I. W. CARAS, L. NITSCH, AND E. RODRIGUEZ. -BOULAN. Glycosylphosphatidylinositol-anchored proteins are preferentially targeted to the basolateral surface in Fischer rat thyroid epithelial cells. J. Cell Biol. 121: 1031-1039, 1993[Abstract/Free Full Text].

394.   ZURZOLO, C., AND W. VAN 'T. HOF, G. VAN MEER, AND E. RODRIGUEZ-BOULAN. VIP21/caveolin, glycosphingolipid clusters and the sorting of glycosylphosphatidylinositol-anchored proteins in epithelial cells. EMBO J. 13: 42-53, 1994[Medline].

0031-9333/99 $15.00 Copyright ©1999 The American Physiological Society