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Physiological Reviews, Vol. 81, No. 3, July 2001, pp. 1353-1392
Copyright ©2001 by the American Physiological Society
Howard Hughes Medical Institute and Departments of Cell Biology and Biochemistry, Duke University Medical Center, Durham, North Carolina; and Department of Biosciences, University of Kent, Canterbury, United Kingdom
Bennett, Vann and
Anthony J. Baines.
Spectrin and Ankyrin-Based Pathways: Metazoan
Inventions for Integrating Cells Into Tissues. Physiol. Rev. 81: 1353-1392, 2001.
The
spectrin-based membrane skeleton of the humble mammalian
erythrocyte has provided biologists with a set of interacting proteins
with diverse roles in organization and survival of cells in metazoan
organisms. This review deals with the molecular physiology of spectrin,
ankyrin, which links spectrin to the anion exchanger, and two
spectrin-associated proteins that promote spectrin interactions with actin: adducin and protein 4.1. The lack of essential functions for these proteins in generic cells grown in culture and the absence of
their genes in the yeast genome have, until recently, limited advances
in understanding their roles outside of erythrocytes. However,
completion of the genomes of simple metazoans and application of
homologous recombination in mice now are providing the first glimpses
of the full scope of physiological roles for spectrin, ankyrin, and
their associated proteins. These functions now include targeting of ion
channels and cell adhesion molecules to specialized compartments within
the plasma membrane and endoplasmic reticulum of striated muscle and
the nervous system, mechanical stabilization at the tissue level based
on transcellular protein assemblies, participation in epithelial
morphogenesis, and orientation of mitotic spindles in asymmetric cell
divisions. These studies, in addition to stretching the erythrocyte
paradigm beyond recognition, also are revealing novel cellular pathways
essential for metazoan life. Examples are ankyrin-dependent
targeting of proteins to excitable membrane domains in the plasma
membrane and the Ca2+ homeostasis compartment of the
endoplasmic reticulum. Exciting questions for the future relate to the
molecular basis for these pathways and their roles in a clinical
context, either as the basis for disease or more positively as
therapeutic targets.
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