Integrins and Actin Filaments: Reciprocal Regulation of Cell Adhesion and Signaling

Abstract

extracellular matrix focal adhesions ezrin, radixin, and moesin vasodilator-stimulated phosphoprotein Wiskott-Aldrich syndrome protein integrin-linked kinase Integrin adhesion receptors link the extracellular matrix (ECM)1to the actin cytoskeleton and transmit biochemical signals and mechanical force across the plasma membrane. This enables cells to generate traction during migration and exert tension during matrix remodeling (1Choquet D. Felsenfeld D.P. Sheetz M.P. Cell. 1997; 88: 39-48Abstract Full Text Full Text PDF PubMed Scopus (1090) Google Scholar). Cytoskeletal linkages also enable integrins to mediate cell adhesion and regulate cell shape and gene expression (1Choquet D. Felsenfeld D.P. Sheetz M.P. Cell. 1997; 88: 39-48Abstract Full Text Full Text PDF PubMed Scopus (1090) Google Scholar). Here we will summarize the evidence for direct interactions between integrin cytoplasmic tails and specific actin-binding proteins and discuss how these interactions influence cell adhesion, cell spreading, and migration. Integrin α and β subunits are type I transmembrane proteins expressed in surface membranes as heterodimers. Each consists of a large extracellular domain, a single transmembrane segment, and a relatively short cytoplasmic tail. The latter contains anywhere from 20 to 70 amino acid residues, with the notable exception of the much larger β4 tail, which is linked primarily to intermediate filaments instead of actin filaments (2Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1674) Google Scholar). β-Cytoplasmic tails are necessary and sufficient to link integrins to the actin cytoskeleton (2Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1674) Google Scholar). In contrast, there is less evidence to date that α tails are directly linked to the cytoskeleton; indeed the removal of the α1, α4, or αIIb cytoplasmic tail appears to increase β tail-mediated interactions with the cytoskeleton (2Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1674) Google Scholar). Direct binding of the signaling adapter protein paxillin to α4 cytoplasmic tails has recently been demonstrated, and this binding regulates α4β1-mediated cell spreading, migration, and stress fiber formation (3Liu S. Thomas S.M. Woodside D.G. Rose D.M. Kiosses W.B. Pfaff M. Ginsberg M.H. Nature. 1999; 402: 676-681Crossref PubMed Scopus (294) Google Scholar). There is direct biochemical support for the interaction of α and β tails with each other (4Muir T.W. Williams M.J. Ginsberg M.H. Kent S.B.H. Biochemistry. 1994; 33: 7701-7708Crossref PubMed Scopus (84) Google Scholar, 5Haas T.A. Plow E.F. J. Biol. Chem. 1996; 271: 6017-6026Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and for the modulation of this interaction by the binding of ligands to the extracellular domain (6Leisner T.M. Wencel-Drake J.D. Wang W. Lam S.C. J. Biol. Chem. 1999; 274: 12945-12949Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Consequently, regulated changes in the interactions between the α and β tails may affect integrin-cytoskeleton linkages. In addition to mediating integrin linkages with the actin cytoskeleton, β cytoplasmic tails are important for adhesion, spreading, and migration of cells on ECM, processes dependent on an intact actin cytoskeleton. Integrins typically cluster within “matrix adhesions,” sites of close apposition of the cell membrane to the ECM. Matrix adhesions are extremely dynamic and heterogeneous structures with respect to size, composition, and orientation to actin filaments (7Zamir E. Katz B.Z. Aota S. Yamada K.M. Geiger B. Kam Z. J. Cell Sci. 1999; 112: 1655-1669Crossref PubMed Google Scholar, 9Hall A. Science. 1998; 23: 509-514Crossref Scopus (5278) Google Scholar). The largest ones are usually referred to as focal adhesions (FA), which are aligned at the ends of actin stress fibers (2Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1674) Google Scholar, 8Jockusch B.M. Bubeck P. Giehl K. Kroemker M. Moschner J. Rothkegel M. Rudiger M. Schluter K. Stanke G. Winkler J. Annu. Rev. Cell Dev. Biol. 1995; 11: 379-416Crossref PubMed Scopus (432) Google Scholar, 9Hall A. Science. 1998; 23: 509-514Crossref Scopus (5278) Google Scholar). As such, FA represent a morphologically prominent association between integrins and the cytoskeleton, and investigation of integrin targeting to FA has shed light on the mechanisms of integrin-cytoskeleton association. Mutational analysis of the 47-amino acid β1 cytoplasmic tail has identified three clusters of amino acids important for integrin localization to FA, a membrane-proximal region and two conserved NPXY (single-letter amino acid code) motifs (10Reszka A.A. Hayashi Y. Horwitz A.F. J. Cell Biol. 1992; 117: 1321-1330Crossref PubMed Scopus (242) Google S