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Functions of Pulmonary Epithelial Integrins: From Development to Disease

Lung Biology Center, Department of Medicine, University of California, San Francisco, California

ABSTRACT

I. INTRODUCTION TO INTEGRINS

A. Integrins as Adhesion Receptors

B. Integrins as Signaling Receptors

C. Integrins as Components of Mechanotransducers

II. PATTERN OF INTEGRIN EXPRESSION ON AIRWAY EPITHELIAL CELLS

III. ROLE(S) OF INTEGRINS IN REPAIR OF WOUNDED EPITHELIA

A. Integrins Can Serve as Both Positive and Negative Regulators of Cell Proliferation

B. Regulation of Epithelial Cell Survival

IV. CLUES FROM THE EXTRACELLULAR MATRIX IN ESTABLISHING AND RESPONDING TO EPITHELIAL CELL POLARITY

V. INTEGRINS AS RECEPTORS FOR RESPIRATORY PATHOGENS

A. Viruses

B. Bacteria

VI. ROLE(S) OF INTEGRINS IN EPITHELIAL NEOPLASIA

VII. SPECIALIZED ROLES OF SPECIFIC INTEGRINS IN LUNG AND AIRWAY EPITHELIUM

A. {alpha}9{beta}1

B. {alpha}v{beta}6

C. {alpha}v{beta}8

VIII. CONCLUSIONS/FUTURE DIRECTIONS

	ABSTRACT

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	I. INTRODUCTION TO INTEGRINS

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Integrins are a large family of heterodimeric transmembrane glycoproteins that were initially identified as cation-dependent receptors for components of the extracellular matrix (50, 91, 92, 97) and as antigens that increased after prolonged activation of lymphocytes (41–43). The first members of the family were identified biochemically in the mid 1980s by affinity chromatography passing lysates of surface-labeled cells over Sepharose beads cross-linked to the adhesive ligands fibronectin (92) or vitronectin (91) and named the fibronectin receptor and the vitronectin receptor, respectively. Demonstration that cells could utilize these receptors to specifically attach to each of these substrates led to initial hopes that a similar approach might identify a series of individual integrins that would each allow cells to specifically attach to distinct biochemical components of the extracellular matrix. Over the subsequent decade, a combination of biochemical approaches and molecular cloning strategies succeeded in identifying a modest-sized protein family that does allow cells to attach to a wide variety of components of the extracellular matrix. Each integrin is composed of a single -subunit and a single -subunit, and once the nucleotide sequence of a few integrins was solved, it became apparent that -subunits and -subunits each constitute a distinct gene family. Both families have been highly conserved during evolution, with obvious orthologs in Caenorhabditis elegans and Drosophila (53). Thus some core functions of these receptors play critical roles in processes that are shared by all multicellular organisms.

The identification of regions of very high sequence conservation among integrin -subunits and -subunits made this family one of the earliest targets for gene discovery by homology-based polymerase chain reaction amplification (27, 93, 102). Intense application of this approach and traditional methods of purification, amino acid sequencing, and library screening led to the identification of 18 human -subunits and 8 -subunits that can form a total of 24 integrin heterodimers (see Fig. 1). The success of these approaches is supported by the absence of any reports identifying additional integrin subunits from the nearly completed human or murine genome sequences.

View larger version (19K): [in this window] [in a new window]   FIG. 1. The integrin family. Solid lines indicate , pairings that have been identified to date on mammalian cells. Since, despite near completion of the human and murine genomes, no new integrin subunit has been identified in the past 2 years, it is likely that this subunit list is near complete. Additional heterodimeric pairings may remain to be identified.

As noted above, the high sequence conservation among -subunits and -subunits across a broad range of species strongly suggests the existence of core integrin functions that have been retained through millions of years of evolution (53). However, the number of integrin subunits and heterodimers has dramatically expanded in higher organisms, with only 2 integrins in C. elegans and at least 24 in humans. It is thus likely that this family of receptors has been enlisted to carry out a range of specialized functions in complex organisms such as mammals. This hypothesis has received additional support from studies of the effects of inactivation of individual integrin subunit genes in mice (52, 101). Most of the integrin subunits have now been inactivated in mice, and the phenotypes of the resultant animals have been distinct and sometimes quite surprising. Lessons from integrin knock-out mice have been extensively reviewed elsewhere (52, 101), but specific results directly relevant to the roles of integrins in pulmonary epithelial cells will be alluded to throughout this review.

Recently, the first crystal structure for the extracellular domains of an intact integrin has been solved (129, 130). The structure demonstrates the presence of a cation-binding site in an exposed face of the -subunit that coordinates all but one of the free sites on bound cation, leaving a free coordination site to interact with a negatively charged residue in integrin ligands. This finding helps to explain the presence of a negatively charged amino acid within the short peptide sequences that have been identified as critical for integrin binding to ligands (e.g., the aspartic acid residue in the arginine-glycine-aspartic acid sequence recognized by a substantial subset of integrins). The close apposition of this site to the adjacent exposed face of the -subunit helps to explain how the combined effects of both subunits can influence ligand binding specificity. A subset of integrin -subunits also contains an additional inserted domain (I domain) that extends from the -subunit face and can also directly interact with ligands. The crystal structure of a subset of isolated I domains has also been solved and contains a similar cation-coordinating motif (69).

A. Integrins as Adhesion Receptors

The first members of the integrin family were identified through efforts to find the receptors that mediate adhesion to specific components of the extracellular matrix (50, 97). The initial conception of adhesion receptors, and therefore of integrins, was as a form of cellular glue that contributes to the integrity of multicellular tissues and organisms. This core function of integrins does seem to be an important one, since it is shared across evolution from primitive organisms. Indeed, the two integrins present in C. elegans appear to mediate adhesion to two classes of extracellular matrix proteins (laminins and proteins that share the tripeptide recognition motif arginine-glycine-aspartic acid, Ref. 53) and homologs of these C. elegans integrins are present in most higher organisims. Furthermore, the phenotypes of mutations in C. elegans integrins involve a defect in muscle contraction that could be explained by a defect in adhesion. Because of this history, one of the first experiments done after identification of each of the members of the family shown in Figure 1 has been cell adhesion assays, usually beginning with assays of adhesion to culture plates coated with specific matrix components. This approach, combined with affinity chromatography (92) or other cell-free methods to demonstrate direct binding of integins to putative ligands, has been quite successful in identifying members of this family that bind to nearly every major protein component of the extracellular matrix.

B. Integrins as Signaling Receptors

In vitro, integrins have been shown to mediate cell adhesion to a wide variety of extracellular matrix proteins, to cell surface counter-receptors, including members of the immunoglobulin and cadherin families (15), and to members of several other protein families, including growth factors (78) and proteases (8). This diverse repertoire of ligands made it apparent a number of years ago that integrins were not likely to be limited to mediating cell adhesion. Over the past decade, thousands of studies performed in cultured cells and whole animals have made it clear that integrins play central roles in modulating virtually every aspect of cell behavior, including migration, establishment of polarity, growth, survival, and differentiation (18, 35, 51). Furthermore, integrin ligation can have profound effects on expression of a number of other genes (22, 98), including those encoding metalloproteinases (127), milk proteins (110), and cytokines (75). Alveolar epithelial cells increase their expression of the gap junction protein connexin 43 when they are plated on fibronectin (3), an effect that is presumably due to integrin ligation.

Members of the integrin family are expressed in virtually every cell of most multicellular organisms. In adult mammals, most cells constitutively express multiple integrins (21, 74, 85, 107) and simultaneously express more than one receptor for the same ligand. In addition, the same integrins are often expressed on cells with markedly divergent functions. It is thus clear that different integrins can direct divergent cellular responses to a single ligand and that specific integrins perform different functions in different cells. Epithelial cells, in particular, perform a number of in vivo functions that are tightly regulated by integrins (100, 123). These include wound repair, establishment of polarity, differentiation into specialized secretory cells, and modulation of local inflammation. In this review, I will draw heavily on studies of integrins in the airway epithelium, skin, and mammary gland to review some of the emerging information about the functions of integrins on epithelial cells in general and on airway epithelial cells in particular.

It is now clear that integrins do not themselves contain any catalytic activity and are thus unable to independently initiate signaling cascades. Rather, the short cytoplasmic domains of integrin - and -subunits serve as scaffolds for the assembly of multiprotein signaling complexes (see Fig. 2). In this regard, they function in similar fashion to T-cell and B-cell receptors for antigen. The integrins themselves serve as the extracellular detectors in these complexes. The recent solution of the crystal structure of the integrin v3 (129, 130) demonstrates a potential basis for signal initiation, with a massive change in conformation suggested when the integrin is occupied by ligand. Although crystals have thus far been obtained only with truncated integrins composed of - and -subunit extracellular domains, modeling suggests that this conformational change would result in a substantial shift in the orientation of the cytoplasmic domains. Such a change is likely to be the basis for signals initiated (or repressed) by integrin ligation.

View larger version (36K): [in this window] [in a new window]   FIG. 2. Simplified model of integrin signaling complexes. The model depicts the types of components that are organized by integrins at points of close apposition to integrin ligands. These include kinases, such as src family members, dual kinase/adaptor proteins, such as the focal adhesion kinase (FAK), scaffolding proteins, such as paxillin, and links to the actin cytoskeleton, such as -actinin and vinculin.

The list of other proteins contained in integrin signaling complexes is large and rapidly growing (35, 76). One key protein in these complexes is the focal adhesion kinase (FAK) (65). FAK is a 125-kDa protein that binds to integrin -subunit cytoplasmic domains and to multiple other components of focal adhesions and is highly concentrated at these sites. FAK also has binding sites for the SH2 domain of the ras-associated protein Grb2, the SH2 domains of src, phosphatidylinositol-3-kinase and phospholipase C-, and for a number of adaptor proteins that can further expand the potential downstream targets of integrin signaling (18). These include, for example, the proteins crk-associated substrate (CAS) and paxillin, which are themselves adaptors allowing binding of several other signaling intermediates. In this fashion, the potential range of signaling pathways that can be modulated by integrin ligations is greatly expanded. Phosphorylation of FAK and activation of its kinase activity are induced by interaction of multiple integrins with their ligands. FAK phosphorylation and activity can also be regulated by several growth factors (64), suggesting one mechanism by which signals from growth factor receptors and integrins might be integrated (see below).

Additional transmembrane proteins are also components of integrin signaling complexes. These include a large family of proteins (tetraspanins) that each contains four membrane-spanning domains (40). These proteins are emerging as organizers of transmembrane signaling complexes, localizing a subset of integrins and other receptors to the same membrane sites. Tetraspanins bind to integrins through interactions of their extracellular domains (133) but can also participate in initiation of integrin-dependent signals [e.g., protein kinase C activation (140) or phosphorylation of lipid signaling intermediates (132)] through distinct sites in their cytoplasmic domains. Another transmembrane protein that participates in integrin signaling is the so-called integrin-associated protein (IAP) (9, 72). IAP also interacts with a subset of integrins (especially 21 and v3) through one of its extracellular domains (71) but can initiate distinct signals, including activation of G proteins (29), through cytoplasmic sequences.

C. Integrins as Components of Mechanotransducers

In addition to organizing signaling complexes, integrin cytoplasmic domains bind directly to adaptor proteins that themselves bind directly to cellular actin. In this fashion, integrins are ideally positioned to connect changes in cell shape or mechanical stresses applied to cells to initiation of biochemical signals that modify cell behavior (2, 121). It is now clear that many (most?) cells can dramatically change their behavior in response to mechanical deformation. In virtually every case, these responses can be attenuated or abolished by blocking one or more integrin. However, because integrins are required to maintain firm substrate adhesion, and because substrate adhesion itself clearly modulates the direct mechanical effects of deforming extracellular forces, it is not simple to determine whether these effects of integrin blockade reflect direct roles for integrins in mechanotransduction or secondary roles in allowing other receptors or channels to be subjected to deformation (33).

	II. PATTERN OF INTEGRIN EXPRESSION ON AIRWAY EPITHELIAL CELLS

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Although specialized epithelia express unique integrin repertoires, there are broad similarities in the pattern of integrin expression in most surface epithelia. Several groups have characterized the expression of integrins on the epithelial cells that line the conducting airways (see Fig. 3) and alveolar spaces of the lung. Integrin expression is dynamically regulated during lung development (19, 20). At least seven different integrins (21, 31, 64, 91, v5, v6, and v8) are expressed on airway epithelial cells of healthy adults (11, 21, 26, 74, 86, 87, 124). Although the original "fibronectin receptor" 51 is generally not seen on healthy adult airway epithelium in vivo, this integrin is rapidly induced by injury in most epithelia, including in the airways (87). The integrins expressed, and some of their known ligands, are listed in Table 1. Of these, 31 and 64 are the only receptors for matrix proteins known to be present in normal epithelial basement membranes (laminins 5, 10, and 11) (13, 25). However, even with respect to these integrins, the spatial patterns of constitutive expression are distinct. 64 is completely restricted to the basal surface of basal cells, where it serves as a central component of hemidesmosomes (108). In this role, 64 is critical for maintenance of epithelial integrity, since mice homozygous for null mutations of either the 6- or the 4-subunit die soon after birth with severe blistering of the skin (34, 119). The identification of severe blistering in a human infant homozygous for a mutation of the 4-subunit provided further confirmation that 64 plays the same role in humans (80). 31 is concentrated at the basal surface, but is also expressed at lower levels around the lateral and apical surfaces of cells throughout the epithelium (unpublished observations). Mice lacking the 3-subunit have defects in branching morphogenesis in the lung and kidney (66). In addition, these animals have dramatic defects in the structural organization of epithelial basement membranes (23). This finding led to the identification of a direct role for 31 in organizing the basement membrane into an ordered structure. Studies with isolated cells from 3 knock-out mice also demonstrated an important role for 31 in epithelial cell migration (44).

View larger version (28K): [in this window] [in a new window]   FIG. 3. Cartoon demonstrations of the changes in the level and distribution of expression of integrins in the airway epithelium in response to injury. Normal, uninjured epithelium is shown on the left, and a theoretical site of denudation is to the far right. Levels of expression are depicted by the size of the text characters corresponding to individual integrins. Patterns of integrin expression in healthy and injured alveolar epithelial cells have not been as thoroughly evaluated.

21 may also interact with collagen IV present in the basement membrane, but its preferred ligands are other collagen isoforms, especially collagen 1 (62). The diffuse surface expression of this integrin suggests other functions, and possibly other biologically important ligands. It has been suggested that 21 and 31 play roles in homotypic cell-cell interaction in epithelia (14, 106, 113). However, the significance of these findings is uncertain in light of other reports that have not been able to substantiate significant roles for either integrin in homotypic interactions (116, 125, 126) and the absence of any described defects in epithelial cell-cell interactions in mice lacking either 3 (66) or 2 (45).

The other integrins that are expressed on basal airway epithelial cells, 51, 91 (28, 70, 103, 104, 114, 137), v5, v6 (10, 46, 78, 136), and v8 (77, 81), recognize a wide array of ligands that are not components of healthy epithelial basement membranes. Many of the ligands recognized by these integrins [e.g., fibronectin, tenascin C, and osteopontin (10, 104, 136, 137)] are among the most highly induced proteins at sites of epithelial injury (61, 124, 139). Vitronectin, the best characterized ligand for v5, is principally a plasma protein and is thus also likely to be enriched in the airways after injury or other increases in vascular permeability. These receptors are thus good candidates to serve as sensors that would allow epithelial cells to rapidly detect and respond to the changes in the extracellular matrix that accompany lung and airway inflammation and injury.

	III. ROLE(S) OF INTEGRINS IN REPAIR OF WOUNDED EPITHELIA

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Surface epithelia all have the capacity to repair areas of denudation. This repair process involves at least three functional changes in the epithelial cells themselves: spreading, migration, and proliferation. Each of these processes requires the participation of integrins. The effects of wounding on the local expression of integrins and their ligands have been most extensively studied in squamous epithelia, such as the skin. Cutaneous wounds contain a provisional matrix that is rich in the integrin ligands fibronectin, osteopontin, and tenascin. In response to epithelial injury, there are dramatic changes in the spatial distribution and level of expression of epithelial integrins. Expression of 21, 31, 51, 64, v5, and v6 is dramatically upregulated along the injured surface (6, 31, 68). Tightly regulated spatial and temporal patterns of expression of each of these integrins have suggested that each of them might play a unique role in orchestrating the normal healing of injured epithelium. However, there must also be substantial redundancy in this process, since inactivation of single integrins [e.g., v5 (47) or v6] or even two integrins simultaneously (e.g., v5 and v6; unpublished observations) does not lead to significant impairment in the rate or quality of cutaneous wound healing.

The most careful study of the effects of airway epithelial wounding on integrin expression was performed utilizing human bronchial grafts placed under the skin of SCID mice (87). In this system, the pattern of integrin expression seen in the absence of injury was quite similar to the pattern seen in normal human airways. After injury, the most prominent changes were upregulation of expression of 51, v5, and v6 along the wounded edge. As in cutaneous wounds, 21 and 6-containing integrins were diffusely expressed on cells above the basal layer. The relevance of these findings to in vivo injury in humans was confirmed by the observation that integrin expression in airways from patients with cystic fibrosis was similar to that seen in the injured xenografts (87).

A. Integrins Can Serve as Both Positive and Negative Regulators of Cell Proliferation

Integrins also play a critical role in regulating cell proliferation (38, 39). Most adherent cells are incapable of proliferating without signals from the extracellular matrix, signals that are transmitted by integrins. Integrins are frequently enriched in membrane microdomains that are also enriched for other cell surface receptors (e.g., growth factor receptors) that contribute to cell proliferation. These sites include structures called focal adhesions, regions of close apposition to the underlying matrix, that are organized around links between integrins and the ends of actin filaments and include a large number of adaptor proteins, signaling kinases, and other components of intracellular signaling pathways (18, 35, 76, 89). Although signals initiated by integrins have been shown to enhance cell proliferation under in vitro conditions without addition of exogenous, soluble growth factors, it is likely that these results are explained in part by autologous production of growth factors by the cultured cells. Ligation of integrins can activate several kinases known to be activated by growth factor receptors, including src, ras (99), and mitogen-activated protein kinases (17). A specific subset of integrins (including 11, 51, and v3) can induce or enhance cell proliferation through interaction of the integrin -subunit cytoplasmic domain with caveolin-1, a membrane protein that plays a role in organizing membrane microdomains. In this pathway, caveolin-1 recruits the src family kinases, yes or fyn, which recruit the adaptor protein shc that in turn leads to recruitment and activation of the well-characterized Ras pathway (122).

Integrins can regulate both increases and decreases in cell proliferation. Several studies have suggested that overexpression of the fibronectin receptor 51 results in inhibition of proliferation (36, 112, 120). One mechanism by which such inhibition occurs has been demonstrated in studies utilizing the colon carcinoma cell line HT-29, a cell line that normally does not express this integrin. Heterologous expression of 51 in these cells diminished their proliferative capacity, an effect that appeared to be mediated by induction of the growth arrest specific gene gas-1, a gene known to be involved in the induction of cellular quiescence (120). Interestingly, this effect was a consequence of expression of unligated integrin, since plating of transfected cells on dishes coated with the 51 ligand fibronectin reversed gas-1 induction and growth inhibition. If a similar pathway is operative in normal epithelial cells, the combined effects of the growth-promoting role of ligated integrin and the growth inhibitory role of unligated integrin would provide an elegant mechanism by which cells in normal adult epithelia (which would not be in contact with fibronectin) are kept out of the cell cycle, but cells as sites of injury (where fibronectin in greatly enriched) can be stimulated to proliferate.

The biological significance of integrin-mediated epithelial cell proliferation has been most extensively examined in the skin (123). Basal keratinocytes in the skin can be divided into three populations based on analysis of proliferative capacity: stem cells, transit-amplifying cells, and committed cells. Stem cells have a high capacity for continued proliferation; transit-amplifying cells have the capacity to undergo a few rounds of proliferation, but usually divide to form daughter cells that permanently withdraw from the cell cycle and undergo terminal differentiation; and committed cells are already permanently withdrawn from the cell cycle. Stem cells can be identified, and sorted in vitro, based on higher levels of expression of 1-integrins (59, 60). Furthermore, in committed cells, integrin function is inhibited, and integrins are lost from the cell surface as keratinocytes move upward away from the basement membrane. The in vivo significance of these changes in integrin expression and function is apparent from the observation that expression of integrin -subunit partners of 1 in the suprabasal cells of the epidermis of transgenic mice produces a hyperproliferative phenotype reminiscent of the hyperproliferative skin disease psoriasis (12).

B. Regulation of Epithelial Cell Survival

Nontransformed epithelial cells cannot survive in the absence of anchorage to the extracellular matrix and die by apoptosis soon after detachment, a process that has been termed anoikis (30). This process, like the withdrawal of growth and survival factors from other primary cells, is mediated, at least in part, by activation of a cascade of caspase proteases that lead to rapid and efficient cell death. Epithelial cells are thus primed to activate a classical caspase-mediated execution program and require input from ligated integrins to negatively regulate this program. Anoikis likely plays the important role of preventing detached epithelial cells in hollow organs like the lung or gastrointestinal tract from reattaching at inappropriate sites. However, anoikis does not appear to be a universal feature of all epithelia. For example, rather than die in this absence of input from integrins, keratinocytes terminally differentiate and begin the process of keratinization (123). In the mammary gland, where involution is a normal phenomenon that follows termination of breast-feeding, apoptosis in the involuting gland is associated with degradation of the stromal matrix by metalloproteinases, a process that also presumably results in unligated integrins. Indeed, in this system, apoptosis can be induced by either antibodies to 1-integrins or by overexpression of the matrix-degrading protease stromelysin-1 in the absence of obvious cell detachment (5). A similar process has been described for endothelial cells (73), which could also cause serious problems if they were capable of surviving detachment and reattachment. In endothelial cells, one pathway for inducing rapid cell death in response to unligated integrin involves direct association of the cytoplasmic domain of the integrin 3-subunit and the initiator caspase caspase 8 (111). A more general pathway appears to involve activation of a caspase 8-mediated execution program that is downstream of activation of protein kinase A by unligated integrins. In endothelial cells, individual unligated integrins can induce this apoptosis pathway, even in cells that remain adherent with other integrins ligated (63).

	IV. CLUES FROM THE EXTRACELLULAR MATRIX IN ESTABLISHING AND RESPONDING TO EPITHELIAL CELL POLARITY

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In vivo, surface epithelial cells, including those lining the conducting airways and alveoli of the lung, are polarized and establish specialized structures along their basal, lateral, and apical surfaces. The establishment of appropriate epithelial polarity requires input from integrins (84, 95, 105). In most epithelia, normal polarity is principally dependent on interactions of integrins with the basement membrane constituent laminin (83, 105). Furthermore, many of the normal differentiated functions of epithelial cells cannot be induced in nonpolarized cultures (110, 118). Considerable insight into the mechanisms underlying establishment of polarity has come from studies of mammary gland epithelial cells. In tissue culture, these cells can be induced to form polarized glandlike structures with a central lumen by overlaying cultures with epithelial derived basement membrane proteins, or with purified laminin (79). Only under these circumstances will mammary epithelial cells fully differentiate in response to lactogenic hormones. These responses to laminin are mediated by input from both 31 and 64 integrins and require input from nonintegrin receptors as well (79).

Renal epithelial cells [for example, Mardin-Darby canine kidney (MDCK) cells] can also be induced to form polarized structures containing an apical epithelium facing a lumen if they are plated in a three-dimensional culture environment. In this case, MDCK cells produce their own laminin and organize it into a basement membrane along the basal surface utilizing the integrin 31. Recent studies utilizing inducible forms of the small GTPase Rac1 have demonstrated a critical role for Rac1-induced reorganization of the actin cytoskeleton in establishing epithelial polarity (83). Although airway epithelial cells have not been directly studied in as much detail, a similar role for polarity in secretory cell differentialtion has been demonstrated in serous cells derived from airway submucosal glands, which clearly require input from a 1-integrin and laminin to express their differentiated secretory cell phenotype (118).

	V. INTEGRINS AS RECEPTORS FOR RESPIRATORY PATHOGENS

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A. Viruses

Viruses and other microorganisms that infect mammals frequently utilize mammalian cell surface receptors to attach to and enter host cells. Integrins are among the important targets used for this purpose (56). At least three of the integrins expressed on airway epithelial cells play important roles in infection of these cells by viruses. 21 serves as an Echovirus receptor, mediated by direct binding of proteins in the virus coat to the ligand-binding insertional domain of the 2 subunit (4). v5 is one of several adenovirus receptors (128). In cultured cells, v5 has been shown to mediate productive adenovirus infection through its dual roles in facilitating viral internalization and subsequent escape from endosomes (128). Areas of normal airway epithelium, where v5 is generally not present on the luminal surface, are more resistant to adenoviral infection and transduction with adenovirally encoded transgenes than are injured areas in which this integrin is expressed on the luminal surface of remaining basal cells (37). This finding led to the suggestion that access to v5 might be a critical determinant of susceptibility to adenoviral infection and adenoviral gene delivery. However, cells from the airways of 5 knock-out mice are as susceptible to adenoviral infection as cells from wild-type mice, demonstrating that the roles of this integrin can be effectively performed by other cell surface receptors. At least three integrins, v3, v6 (58), and v1 (57), have been shown to be capable of supporting infection by the foot and mouth disease virus that has recently been the cause of an economically costly epidemic in the United Kingdom. Of these, v6 is the only one known to be expressed on the mucosal epithelial cells that are the primary site of infection by this virus.

B. Bacteria

Integrins can also mediate adhesion and internalization of bacteria into epithelial cells. The best-described interaction of bacteria with epithelial integrins involves infection with the gastrointestinal pathogen Yersenia pseudotuberculosis (54, 55). Yersenia expresses a protein called invasin on its cell wall that serves as a specific ligand for 1-integrins. Binding of invasin to integrins on M cells in the gut epithelium is an absolute requirement for uptake of the bacteria into these cells and plays a central role in Listeria pathogenesis (54). The best-characterized role for interactions between integrins and bacteria in the respiratory epithelium involves the preferential attachment of the respiratory pathogen Pseudomonas aeruginosa to sites of epithelial injury. In that case, attachment is not direct, but rather utilizes the extracellular matrix protein fibronectin as a bridge (96). Fibronectin binds to an as yet unidentified Pseudomonas surface protein and simultaneously fibronectin binds to 51 on epithelial cells. Because little 51 is expressed on respiratory epithelial cells in the absence of injury, and little integrin at all is expressed on the uninjured luminal surface, epithelial injury greatly enhances Pseudomonas attachment.

	VI. ROLE(S) OF INTEGRINS IN EPITHELIAL NEOPLASIA

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Initial efforts to understand the roles that integrins might play in the development of epithelial tumors involved descriptive immunohistochemistry. It soon became apparent, however, that the changes in integrin protein expression in epithelial tumors are complex and heterogeneous. As noted above, many primary epithelial cells undergo apoptosis in response to loss of integrin ligation, but this response is lost in most epithelial tumors, so carcinomas do not require input from integrins for survival. Similarly, loss of anchorage dependence (i.e., integrin dependence) for growth is a common feature of carcinomas. In their role in anchoring epithelial cells to the normal basement membrane, integrins could also impede tumor cell migration and subsequent invasion and metastasis. Because tumors can survive and grow without integrins and may be impeded by integrins in invasion and metastasis, it is not surprising that a general decrease in integrin expression is seen in many invasive carcinomas. However, because integrins can also enhance growth factor-mediated proliferation, provide traction for cell migration through the extracellular matrix, and localize matrix-degrading proteases to the leading edge of migrating cells (8), it is also not surprising that many epithelial tumors utilize integrins to enhance their growth and/or invasion. In at least one case, the same integrin (64) that restricts movement of normal epithelial cells through anchorage of hemidesmosomes is utilized by malignant epithelial cells to support migration and invasion (16, 32, 94). In that case, a key step is the relocalization of 64 from hemidesmosomes to the leading edge. In this case, tumor cells are apparently taking advantage of a normal homeostatic mechanism through which 64 is similarly relocalized to support migration of epithelial cells at the leading edge of wounds.

The integrin v6 also appears to modify malignant transformation and enhance the growth and invasion of epithelial tumors (131). In this case, the same integrin affects carcinogenesis growth and invasion through distinct mechanisms. In the early stages of malignant transformation, the ability of this integrin to locally activate transforming growth factor (TGF)- (see below) would be expected to inhibit carcinogenesis. However, independently of TGF- activation, the cytoplasmic domain of the 6 subunit specifically supports tumor cell proliferation, both in vivo and in vitro (1), and also induces expression of the metalloprotease MMP-9 (82, 117), which enhances tumor cell invasion. Thus this integrin plays distinct roles at different steps in the process of malignant transformation and tumor growth and invasion.

	VII. SPECIALIZED ROLES OF SPECIFIC INTEGRINS IN LUNG AND AIRWAY EPITHELIUM

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A. 91

The integrin 9-subunit was initially identified by homology polymerase chain reaction amplification from primary cultures of guinea pig airway epithelial cells (27). This subunit is present in a single integrin, 91, that is diffusely expressed on the surface of basal airway epithelial cells (86). 91 was first identified as a receptor for the provisional matrix protein tenascin C, where it binds to a novel sequence adjacent to an exposed loop that contains the arginine-glycine-aspartic acid site that serves as a ligand for at least five other integrins (134). It is now clear that 91 is a rather promiscuous integrin that can bind to a large group of rather diverse ligands, including the provisional matrix protein osteopontin (104, 135), an alternatively spliced region of cellular fibronectin (70), the coagulation protein factor XIII (114), the extracellular enzyme tissue transglutaminase (114), the immunoglobulin family members vascular adhesion molecule-1 (115) and L1-CAM (103), and several members of the ADAMs family of transmembrane metalloproteinases (28). Because mice homozygous for a null mutation of the 9-subunit die soon after birth from chylothorax (an apparent consequence of defective lymphatic development), it has not been possible yet to utilize these mice to directly examine the roles of 91 and each of these ligands in the adult lung or airways (49). Nonetheless, some clues are provided by descriptive studies of the pattern of 91 expression and by studies of its function in vitro on cultured cells.

The observation that 91 is generally expressed on cells with the capacity to proliferate (e.g., the limbic cells of the cornea and the basal cells of the conducting airways and skin), but that 91 expression is rapidly lost in vitro in primary epithelial cultures, suggests that interaction of 91 with one or more of its ligands might be important in maintaining differentiated cells with regenerative capacity in epithelial organs (109). Further clues come from studies demonstrating critical roles for 91 in mediating rapid cell migration of both neutrophils (115) and nonleukocytic cells (138). Studies utilizing heterologously expressed deletion mutants of the 9 cytoplasmic domain and chimeras of 9 and other integrins have identified a short region of the 9 cytoplasmic domain that is directly responsible for the ability of this integrin to enhance cell migration (138). Perhaps this function plays a role in the rapid migration of precursor cells across the diverse ligands present at sites of epithelial denudation. Recent observations have demonstrated that 91 is the preferred receptor for most members of the ADAMs family, a widely expressed family of transmembrane proteases that also contain a so-called disintegrin domain (a binding site for integrins) and a domain that resembles viral fusion peptides. It is tempting to hypothesize that interactions of ADAMs family members with 91 could play a role in modulating either their proteolytic or membrane fusion functions (28).

B. v6

The integrin v6 was initially identified as a receptor for the extracellular matrix proteins fibronectin (10) and tenascin C (90, 136). This integrin is unusual in that its expression is highly restricted to a subset of epithelial cells, including the epithelium lining the conducting airways and alveoli (6, 7, 124). Studies with in situ hybridization and the first developed monoclonal antibodies that specifically recognize this integrin suggested that the integrin was not expressed at these sites in healthy adults. However, the development of better antibodies has made it clear that v6 is constitutively expressed at low levels in uninjured epithelia. However, v6 expression is markedly upregulated on epithelial cells in multiple epithelial organs, including the lung, in response to injury and acute and chronic inflammation (6, 124). One of the first functions identified for this integrin was enhancement of the proliferation of carcinoma cells in three-dimensional cultures and in vivo in nude mice (1). Expression of v6 also induces expression of the matrix-degrading protease MMP-9 (82, 117). These effects are dependent on an 11-amino acid carboxy-terminal sequence within the 6 cytoplasmic domain that is not present in other integrins (1, 24, 82). Because v6 is commonly expressed in carcinomas, especially on cells adjacent to or invading the underlying stroma, v6 might play an important role in the growth, invasion, and/or spread of carcinomas derived from lung epithelial cells.

Introduction of a null mutation of the 6 subunit in mice identified additional functions for this integrin that are likely to be even more important for normal lung homeostasis and responses to lung injury. 6-Subunit knock-out mice develop exaggerated inflammatory responses to injury in the lungs and skin (48) but are protected from one of the usual consequences of lung inflammation, pulmonary fibrosis (78). This phenotype suggested a possible interaction between this integrin and the growth factor TGF-1, since TGF- is a known central regulator of tissue fibrosis, but TGF-1 knock-out mice also develop exaggerated inflammation (67). These observations led to identification of a direct interaction between the v6 integrin and a region of TGF-1 called the latency-associated peptide (LAP) (78). LAP, which is formed by cleavage of the amino terminus of the TGF-1 gene product, normally forms a homodimer which noncovalently associates with a homodimer of the mature, active TGF- (the carboxy-terminal fragment of this same cleavage reaction). In this form, LAP prevents mature TGF- from binding its receptors and inducing TGF- effects. v6 can bind LAP in latent TGF-1 and TGF-3 complexes and alter the confomation of the complexes, effectively activating TGF-1. Importantly, binding of the integrin is not sufficient to activate latent complexes, and this process itself can be activated through a signaling pathway in the integrin-expressing epithelial cell. Furthermore, the conformational change in the latent complex does not appear to release free active TGF-, providing an elegant mechanism to tightly regulate the activity of this potent cytokine both in space and in time (Fig. 4A).

View larger version (27K): [in this window] [in a new window]   FIG. 4. Models of transforming growth factor (TGF)- activation by the integrins v6 (A) and v8 (B). A: integrin v6 binds to the RGD site in TGF-1 or -3 latency-associated peptides (LAP). Binding is not sufficient to induce activation of the latent complex. Activation requires rearrangement of the actin cytoskeleton and allows the active site on TGF- to bind and activate receptors on adjacent cells. B: integrin v8 also binds to the RGD site in TGF-1 or -3 LAP, but in this case binding presents the latent complex to the transmembrane protease MT1MMP, which cleaves LAP and releases active TGF-, which is free to diffuse from the cell surface.

Further studies in 6 knock-out mice demonstrated a role for the v6 integrin in the development of pulmonary edema in two models of acute lung injury (88). Mice lacking this integrin were protected from the pulmonary edema that occurred in wild-type controls following instillation of intratracheal bleomycin or endotoxin. Blockade of TGF- resulted in similar protection in wild-type mice, identifying a role for v6-mediated activation of TGF- in the development of pulmonary edema following acute lung injury, at least in mice.

Analysis of global gene expression in the lungs of wild-type and 6 knock-out mice identified dramatic induction of the macrophage-restricted metalloproteinase MMP12 in the lungs of the 6 knock-out (61). This integrin thus also appears to play an unexpected role in a negative feedback system by which injured epithelial cells can turn off protease expression in macrophages that are likely to be activated in the setting of alveolar injury. Loss of this signal has biologically important consequences, since 6 knock-out mice eventually develop slowly progressive emphysema. This response is completely dependent on induction of MMP12, since mice homozygous for null mutations of MMP12 and the 6-subunit are protected from the development of emphysema (76a).

C. v8

Human airway epithelial cells also express the integrin v8. Until recently, the only known ligand for this integrin was the plasma protein vitronectin (81), and the function(s) of v8 was obscure. In contrast to most integrin -subunits, which contain several functionally important conserved sequence motifs in their short cytoplasmic domains, the 8 cytoplasmic domain is completely unique. Recent studies have demonstrated that v8 is also functionally distinct from most other integrins in that its principal effect on cell proliferation is inhibitory (11). v8-mediated inhibition of cell proliferation is, not surprisingly, directly dependent on sequences within its divergent -subunit cytoplasmic domain. Interestingly, though, v8, like v6, can bind to the LAP of TGF-1 and -3 and activate latent complexes (77). However, the mechanism of TGF- activation by these two integrins is completely different. v6-mediated TGF- activation depends on interaction of sequences in the 6 cytoplasmic domain with the actin cytoskeleton, leads to a local change in conformation of latent complexes without releasing free diffusible active TGF-, and appears not to involve the activity of any known proteases. In contrast, v8-mediated TGF- activation does not require the 8 cytoplasmic domain and does lead to release of free TGF- (Fig. 1B). Furthermore, v8-mediated activation is inhibited by the metalloprotease inhibitor GM6001 and depends on the presence of the transmembrane metalloprotease MT1MMP (77). Thus it appears likely that v8 binds latent complexes and presents them to MT1MMP, which can directly cleave LAP, leading to the release of active TGF-. The biological significance of the simultaneous existence of two distinct pathways for integrin-mediated TGF- activation in airway epithelial cells has not been directly examined. However, possible clues come from the reported patterns of expression of these integrins. v8 is highly expressed in resting airway epithelial cells, but expression is decreased when these cells are placed in culture, after injury, and in most epithelial tumors, all conditions that are associated with epithelial cell proliferation. In contrast, v6 expression is dramatically increased in cultured cells, injured cells, and many carcinomas. Thus one plausible hypothesis is that v8-mediated TGF- activation produces low local concentrations of this cytokine that maintain growth arrest in resting, confluent epithelial cells, an effect that is enhanced by the growth inhibitory effects of the divergent 8 cytoplasmic domain. In contrast, in the setting of injury, v6 serves to spatially concentrate TGF- at sites where it is needed for repair, while the growth-promoting 6 subunit cytoplasmic domain can counteract the normal growth inhibition induced by any active TGF- that is presented to adjacent epithelial cells.

	VIII. CONCLUSIONS/FUTURE DIRECTIONS

Top References

 
The epithelial cells that line conducting airways and alveoli utilize input from integrins for airway branching during development (31) to establish polarity and to organize and remain attached to their basement membrane (31, 64). Because these cells constitutively express at least six other integrins that recognize ligands that are not present in resting healthy airways, but are induced in spatially restricted patterns in response to injury and inflammation, it is likely that epithelial cells utilize these integrins to detect, coordinate, and spatially organize complex responses to airway and lung injury. In addition to serving as detectors and signaling receptors, a subset of airway epithelial integrins also play a direct role as extracellular effectors, by binding to and activating the potent cytokine TGF-. Integrin-mediated TGF- activation is likely to be important in maintaining epithelial quiescence (in the case of v8) and in spatially restricting the effects of this potent cytokine in inducing alveolar flooding and fibrosis after injury (in the case of v6). Dysregulation of integrin function on epithelial cells has already been found to play important roles in acute lung injury, pulmonary fibrosis, and the formation, growth, and spread of carcinomas. Because the physiologically relevant ligands and in vivo functions of many of the integrins expressed on lung epithelial cells have not been fully identified (e.g., for 91), it is likely that additional roles for these receptors in lung development, health, and disease will emerge from further studies of conditional inactivation and in vivo blockade.

Address for reprint requests and other correspondence: D. Sheppard, Univ. of California, San Francisco, Box 0854, San Francisco, CA 94143-0854 (E-mail: deans{at}itsa.ucsf.edu).

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