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J. Biol. Chem., Vol. 275, Issue 30, 22607-22610, July 28, 2000

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MINIREVIEW
Integrins and Actin Filaments: Reciprocal Regulation of Cell Adhesion and Signaling^*

David A. Calderwood, Sanford J. Shattil^§, and Mark H. Ginsberg^¶

From the  Department of Vascular Biology and ^§ Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

	INTRODUCTION

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

Integrin adhesion receptors link the extracellular matrix (ECM)¹ to 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 (1). Cytoskeletal linkages also enable integrins to mediate cell adhesion and regulate cell shape and gene expression (1). 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.

	Role of Integrin Cytoplasmic Tails in Integrin-Cytoskeleton Linkages

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

Integrin  and  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 ₄ tail, which is linked primarily to intermediate filaments instead of actin filaments (2). -Cytoplasmic tails are necessary and sufficient to link integrins to the actin cytoskeleton (2). In contrast, there is less evidence to date that  tails are directly linked to the cytoskeleton; indeed the removal of the ₁, ₄, or _IIb cytoplasmic tail appears to increase  tail-mediated interactions with the cytoskeleton (2). Direct binding of the signaling adapter protein paxillin to ₄ cytoplasmic tails has recently been demonstrated, and this binding regulates ₄₁-mediated cell spreading, migration, and stress fiber formation (3). There is direct biochemical support for the interaction of  and  tails with each other (4, 5) and for the modulation of this interaction by the binding of ligands to the extracellular domain (6). Consequently, regulated changes in the interactions between the  and  tails may affect integrin-cytoskeleton linkages.

In addition to mediating integrin linkages with the actin cytoskeleton,  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 (7, 9). The largest ones are usually referred to as focal adhesions (FA), which are aligned at the ends of actin stress fibers (2, 8, 9). 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 ₁ 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 (10). Similar motifs in the ₃ cytoplasmic tail are important for localization of ₃ integrins to FA (11). An additional Thr-containing motif between the two NPXY sites has also been implicated in ₂ integrin-cytoskeleton linkages (12).

	Specific Integrin-Cytoskeleton Linkages

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

Integrins are linked to actin filaments by specific actin-binding proteins, and there is now an emerging consensus concerning which proteins are involved (Fig. 1).

View larger version (23K): [in this window] [in a new window]   Fig. 1.   Models of the physical links between integrins and F-actin. When known, the modular architecture of the linking proteins is shown based on domain assignments by the SMART program (13). The  integrin tail is depicted binding to ERM domains within the talin head domain; however, integrin-binding sites have also been identified in the rod domain. The spectrin repeats within the -actinin rod domain mediate binding to the integrin  tail; however, it is not known which of the three repeats contains the binding site. Filamin binds integrins via C-terminal filamin repeats; however, the exact binding site has not yet been determined.

Talin-mediated Linkages-- Talin is composed of two ~270-kDa subunits arranged as an anti-parallel homodimer (8), and it co-localizes with integrins at certain sites of cell-substratum contact. Talin is a major structural component of FA along with actin and vinculin. It consists of an N-terminal ~50-kDa globular head domain, which includes an ~200-amino acid region with homology to the ezrin, radixin, and moesin (ERM) family of proteins, and an ~220-kDa, C-terminal rod domain containing a conserved ILWEQ actin-binding domain (8, 13). Talin contains binding sites for actin, vinculin, focal adhesion kinase, phospholipids, and the transmembrane protein laylin (8, 14). Talin was the first actin-binding protein shown to directly bind integrins and was proposed to mediate the link to the actin cytoskeleton (2). Talin binds to ₁, ₂, and ₃ and more weakly to ₇ integrin cytoplasmic tails (15-18). Talin accumulation is an early step in FA formation and requires integrins but not vinculin (19). Microinjection of antibodies to talin or talin antisense RNA disrupts stress fibers and inhibits adhesion, spreading, and migration of fibroblasts and HeLa cells (8, 20).

The significance of talin for integrin function has been underscored by studies of talin-null ES cells, which exhibit extensive membrane blebbing, defects in cell adhesion and spreading, and a failure to assemble FA or stress fibers (21). These results suggest that talin is required for the integrin-cytoskeleton associations needed for FA and stress fiber formation. However, undifferentiated talin-null ES cells also express reduced levels of ₁ integrin, vinculin, and -actinin, which may contribute to the phenotype. Following differentiation of talin-null ES cells, only two morphologically distinct cell types emerged, and no organized tissues were formed (21). The differentiated cells expressed normal levels of ₁ integrin and vinculin and were capable of spreading and forming actin filaments and FA-like structures, indicating that in a subset of differentiated cell types, intact talin is dispensable for maintenance of ₁ integrin expression and FA assembly.

Integrin-binding sites have been localized to both the talin-head and rod domains (17, 18), suggesting that binding of two or more integrin  tails to the talin dimer may facilitate integrin clustering (Fig. 1). Binding of both the head and rod domains are inhibited by Tyr to Ala mutations in the membrane-proximal NPXY motif of ₁ and ₃ integrins (15, 17, 22), consistent with the failure of integrins expressing this mutation to localize to FA (10, 11). In v-Src-transformed cells, which exhibit reduced cell adhesion and a disorganized cytoskeleton, the NPXY motif in the ₁ tail is phosphorylated on tyrosine, and talin binding is inhibited (23). Furthermore, synthetic peptides spanning the NPXY motif bind purified talin and inhibit talin binding to ₁ (22, 23). Thus, the talin-binding site in the ₁ tail includes this sequence.

However, other regions of the  tail are likely to contribute to the interaction with talin because the NPXY motif is highly conserved between integrin  subunits, but talin displays differential binding to various integrin  tails (15). Indeed, deletion of the C-terminal 13 amino acids of the ₁ cytoplasmic tail, which leaves the membrane-proximal NPXY site intact, inhibits both talin binding in vitro and co-localization of talin and actin with clustered ₁ integrins in vivo (22, 24). In contrast, deletion of only the four most C-terminal amino acids from ₁ has no effect on talin binding or recruitment of talin and actin to sites of clustered integrins (22, 24). Furthermore, a recent report concluded that talin could bind specifically to peptides corresponding to the membrane-proximal sequence of the ₃ tail (18). Thus, further work is required to determine the precise mode of interaction between integrin  tails and talin.

Filamin-mediated Linkages-- Three distinct filamin genes have been reported, and alternative splicing allows for additional isoforms (25). Filamins are actin filament cross-linking proteins composed of two parallel 280-kDa subunits. Each subunit contains an N-terminal actin-binding domain composed of two calponin homology domains, followed by 23 repeating domains (8, 13). Depending on the filamin:F-actin ratio, filamin reinforces loose microfilament nets such as those found in the cell cortex (Fig. 1) or tightly packed bundles as found in stress fibers (8). Filamin also binds to the cytoplasmic domains of transmembrane proteins (e.g. GP Ib) and to intracellular signaling molecules (e.g. RalA) (25, 26). Filamin localizes to the cortical actin cytoskeleton and along the length of stress fibers but is also found in some FA (8).

_1A, ₂, ₃, ₇, and to a lesser extent _1D integrin tails can bind filamin, and Tyr to Ala point mutations in the membrane-proximal ₁ NPXY motif inhibit binding (15, 27). Both filamin and F-actin are recruited to ₁-containing FA in response to mechanical stress, but F-actin recruitment does not take place in melanoma cells lacking filamin (28). The gene encoding human filamin-1 is located on the X chromosome, and mutations of this gene are associated with periventricular heterotopia, indicating a requirement for filamin-1 in neuronal migration during brain development (26). Loss of filamin-1 expression in neuronal or melanocytic cells results in impaired migration and altered morphology (26, 29). However, filamin-1 null melanocytic cells also have reduced levels of many cell surface receptors, including  integrins (30), which may account for some of these phenotypes.

-Actinin-mediated Linkages-- -Actinin is another homodimeric actin-binding protein localized to FA (8). Non-muscle -actinin monomers are ~100-kDa rodlike proteins containing three functional domains: an N-terminal actin-binding domain composed of two calponin homology domains, a central region of four spectrin-like repeats, and a C-terminal domain containing two EF hands. At least two -actinin genes and alternative splicing allow for production of a number of -actinin isoforms. In addition to binding F-actin, -actinin binds the FA proteins vinculin, zyxin, and ₁, ₂, and ₃ integrins (2, 8) (Figs. 1 and 2). -Actinin targets to FA in microinjected cells and in a cell-free system, apparently by interaction with  cytoplasmic tails (31, 32). The binding sites for -actinin have been localized to the membrane-proximal half of the ₁ or ₂ integrin tail, and binding to ₂ is negatively regulated by sequences in the C-terminal region of the tail (16). The membrane-proximal location of the -actinin-binding site within  tails is consistent with the observation that antibody-mediated clustering of ₁ integrins lacking the C-terminal 13 amino acids also induces clustering of -actinin (24). However, -actinin binding to clustered integrins is not sufficient to recruit F-actin (24, 32). Overexpression of -actinin in fibroblasts leads to more stable attachment sites whereas isolated integrin-binding fragments of -actinin disrupt stress fibers, FA, and shear-induced mechanical signaling in fibroblasts and osteoblasts (8, 31).

View larger version (20K): [in this window] [in a new window]   Fig. 2.   Models for integrin localization of actin nucleation and polymerization. VASP, profilin, Arp2/3, and WASP may regulate actin filament assembly at sites of integrin-ECM contact. Nck-2-WASP interactions have not been demonstrated but are hypothesized on the basis of Nck-1 binding to WASP.

Other Integrin-binding Cytoskeletal Proteins-- Recent reports suggest that additional proteins may serve as direct links between integrin tails and the cytoskeleton. In platelets, the two tyrosines in the ₃ cytoplasmic tail become phosphorylated during agonist-induced cell aggregation (33). Synthetic peptides corresponding to the tyrosine-phosphorylated ₃ tail bind to the actin-binding protein, myosin (34). This interaction may be physiologically relevant because conversion of the two ₃ tail tyrosines to phenylalanine is associated with a mild bleeding phenotype in mice (33). Skelemin, a cytoskeletal M-band protein, can bind ₁ and ₃ but not ₂ tails expressed in vitro (35). Skelemin co-localizes with stably expressed _IIb3 under some conditions, and microinjection of the integrin-binding domain of skelemin causes myoblasts to round up (35). Whether these interactions represent widespread or specialized cases of integrin-cytoskeleton linkages remains to be determined.

Vinculin-mediated Interactions-- Vinculin, an ~120-kDa molecule, is one of the most abundant FA proteins and interacts with F-actin, talin, -actinin, paxillin, and vasodilator-stimulated phosphoprotein (VASP) (8, 36). Vinculin does not bind directly to integrins but may be recruited by integrin-bound talin or -actinin (Fig. 1). However, although reduced levels of vinculin result in a reduction in the mechanical stiffness of the integrin-cytoskeleton linkage and increased cell motility, vinculin-null ES cells can differentiate in vitro into a variety of cell types (37) and can spread and form talin-rich FA and stress fibers (21). Thus, despite ubiquitous expression, vinculin is not absolutely required for some integrin-F-actin linkages and is likely to function as a molecular bridge to stabilize pre-existing linkages.

	Inside-out Integrin Signaling: Role of Cytoskeletal Proteins

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

Integrins are subject to rapid regulation of their ligand binding activity by intracellular signals, and this has been termed inside-out signaling or integrin activation (38). Inside-out signaling may act by 1) inducing conformational changes in and altering the affinity of integrin heterodimers and 2) clustering heterodimers into multimers. These forms of modulation are not mutually exclusive, and they may operate in a complementary manner to control both ligand binding and postligand binding events (39).

Inside-out signals to integrins originate from diverse plasma membrane receptors. As with signal propagation to other parts of the cell, these excitatory receptors presumably regulate integrins by triggering post-translational changes, such as phosphorylation/dephosphorylation, that affect the activity and/or subcellular localization of key enzymes and substrates in integrin-regulatory pathways (40). Thus, cytoskeletal proteins could modulate inside-out signaling by promoting the activity of integrin-regulatory molecules and/or by controlling their proximity to integrin cytoplasmic tails (38). Alternatively, or in addition, certain cytoskeletal proteins might be able to modulate the integrin activation state directly as the result of regulated changes in integrin-cytoskeleton linkages. Furthermore, in cases where integrins bind to counter-receptors on other cells instead of ECM, integrin avidity may be influenced by cytoskeleton-driven alignment of the membranes on the opposing cells (41).

As a possible example of regulation of integrin function by cytoskeletal linkages, ₂ integrins from unstimulated neutrophils do not engage ₂ ligands, and they co-immunoprecipitate with talin but not -actinin (16). However, cell activation by fMet-Leu-Phe induces ligand binding to the ₂ integrins and stimulates talin proteolysis and dissociation from ₂ in a manner dependent on the calcium-dependent protease, calpain. During a later phase of cell activation, ₂ now co-precipitates with -actinin and not talin, an association hypothesized to result from a change in conformation of the ₂ cytoplasmic tail (16). In this scheme, integrin activation would be initiated by calpain-dependent release of one integrin-cytoskeleton linkage and later reinforced by another. This overall model may also apply to activation of other integrins, but the precise details may differ. For example, calpain activation in platelets is a relatively late event, occurring after the initial phase of _IIb3 activation, and it is responsible for cleavage of numerous cytoskeletal and signaling proteins, including the ₃ cytoplasmic tail itself (42).

Regulated interactions between cytoskeletal proteins and integrin cytoplasmic tails might also explain why _L2 in phorbol ester-stimulated Epstein-Barr virus-transformed B lymphocytes exhibits a 10-fold increase in random diffusion rate, a change that correlates with increased cell adhesion to ICAM-1 (41). Treatment of these cells with low concentrations of cytochalasin D, which caps actin filaments preventing further polymerization, has the same effect, whereas higher concentrations of cytochalasin D inhibit cell adhesion. Similarly, exposure of peripheral blood lymphocytes to cytochalasins induces clustering of _L2 and adhesion of the cells to ICAM-1 (43), and the same is observed in peripheral blood-derived T lymphoblasts after cross-linking of the T cell receptor (44). In leukocytes, it has been proposed that L-plastin, an actin-bundling protein, may modulate the avidity of _M2 in a manner dependent on L-plastin phosphorylation by protein kinase C (45).

Cytoskeletal linkages may also be involved in the activation of _IIb3 in platelets. For example, in unstimulated platelets a subpopulation of _IIb3 is associated with the membrane cytoskeleton, and relatively low concentrations of cytochalasin D or latrunculin A, which blocks polymerization of actin monomers, induce ligand binding to _IIb3 (46). This effect requires a stimulus, such as ADP released from the washed platelets, which the authors suggest might increase actin turnover by binding to purinergic receptors and stimulating the actin filament-severing activity of gelsolin and the filament-disassembly activity of ADF-cofilin.

Rho family GTPases play a prominent role in actin polymerization and reorganization during cell migration (9), and it is logical to consider whether they are directly involved in promoting integrin activation. In fibroblasts, activation of Cdc42 and Rac is associated with the formation of focal complexes (9), but their effects on ligand binding to integrins has not been studied. Inhibition of Rho with C3 exoenzyme decreases ₂ and ₃ integrin-dependent aggregation of leukocytes and platelets, respectively (2). However, in adherent platelets inhibition of Rho with C3 exoenzyme blocks certain postligand binding events, such as the formation of vinculin patches and actin cables, but it has no effect on agonist-induced activation and ligand binding to _IIb3 (47). Similarly, C3 exoenzyme blocks the formation of FA and stress fibers in fibroblasts, but it has no significant effect on the activation state of ₅₁ (48). In these cases, therefore, Rho may function to regulate cell adhesion through effects on postligand binding events (9).

	Integrin-associated Proteins Regulate Actin Filament Assembly

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

The studies pointing to a role for actin and actin-binding proteins in regulating integrin function have coincided with remarkable recent advances in understanding the regulation of actin filament assembly. Integrins may provide the appropriate subcellular locale for actin filament assembly and organization in adherent and migratory cells by virtue of integrin-cytoskeleton linkages and integrin-triggered outside-in signals. In this context, several proteins implicated in the regulation of actin assembly are either components of FA or interact with cytoskeletal proteins that are linked to integrin  cytoplasmic tails.

The Mena/VASP Family-- Members of this protein family, which include VASP, the Drosophila protein Enabled (Ena), its mammalian orthologue Mena, and Evl (Ena-VASP-like), contain conserved N- and C-terminal domains (EVH1 and EVH2) separated by a proline-rich domain that binds profilin and SH3 domains (49, 50) (Fig. 2). The VASP EVH2 domain mediates tetramerization of the molecule, F-actin binding, and bundle formation (51). The EVH1 domain mediates targeting to FA by binding to proline-rich motifs in zyxin and vinculin (Fig. 2) and binds to the ActA movement protein of the intracellular bacteria Listeria monocytogenes (49, 50). Mena/VASP proteins are localized to sites of actin assembly, such as FA and membrane ruffles, and are concentrated at the tips of rapidly moving lamellipodia and at the focal contacts at their base (52). This localization of VASP is consistent with its proposed role in linking membrane proteins, which presumably include integrins, to polymerizing actin.

VASP is also a substrate for cyclic AMP-dependent protein kinase A and cyclic GMP-dependent protein kinase G. In platelets, cyclic AMP and cyclic GMP are potent inhibitors of agonist-induced activation of _IIb3, and phosphorylation of VASP by protein kinase A or protein kinase G correlates with inhibition of fibrinogen binding to activated platelets (53). There may be a causal relationship between VASP phosphorylation and inhibition of _IIb3 activation because VASP-deficient murine platelets show enhanced agonist-induced fibrinogen binding to _IIb3 and the inhibitory effects of cyclic nucleotides on fibrinogen binding are reduced (49, 53).

Investigation of ActA has provided insight into eukaryotic mechanisms for regulating actin filament assembly (54). This has led to a model in which Mena/VASP proteins are targeted to FA by binding to zyxin or vinculin, which in turn bind -actinin or talin. This would allow Mena/VASP to bind to actin filaments via their EVH2 domains or through profilin that is bound to oligomerized Mena/VASP (Fig. 2). Microinjection of peptides that inhibit EVH-1 binding to vinculin and zyxin displace Mena/VASP from FA and cause retraction of membrane protrusions. Furthermore, a recessive lethal Ena allele contains a point mutation that impairs zyxin binding in vitro. Consequently, Mena/VASP function probably requires its targeting to FA via interactions with -actinin (54). Surprisingly, mice deficient in VASP or Mena are viable, fertile, and display relatively mild phenotypes, which may reflect functional compensation by related family members (49, 50, 53). Mena-deficient mice that are also heterozygous for a profilin-1 deletion die perinatally. Thus, a 50% reduction in profilin-1 sensitizes animals to loss of Mena, consistent with their cooperation in regulating the actin cytoskeleton (50).

In summary, Mena/VASP proteins appear to contribute to F-actin binding at FA but are not required for FA assembly or maintenance. Mena/VASP proteins play important roles in regulating actin filament assembly, particularly at the leading edge of migrating cells, and Mena/VASP associations with integrins, although indirect, may target actin polymerization to fresh sites of integrin-ECM contact.

Arp2/3 and WASP-- The studies on Listeria, which highlighted the role of Mena/VASP, also revealed a requirement for the Arp2/3 complex for actin polymerization (54, 55). This complex consists of seven proteins and co-localizes with Mena/VASP at the leading edges of cells to promote the assembly of actin filament networks (55). Hence, recruitment of Arp2/3 to focal contacts containing integrin-associated Mena/VASP may contribute to actin assembly at sites of ECM contact (54). Machesky and Insall (55) describe a model for the activation of Arp2/3 by extracellular signals, leading to regulated assembly of actin filaments allowing production of force for cell motility and shape changes. A critical question in this model is how the Arp2/3 complex becomes localized at sites where actin polymerization is required, such as lamellipodia.

Identification of members of the WASP (Wiskott-Aldrich syndrome protein) family as Arp2/3-binding proteins (55) suggests a complex multimolecular assembly, which may bring Arp2/3 into contact with integrin-associated Mena/VASP (Fig. 2). Expression of WASP appears to be limited to cells of hematopoietic lineage; however, two family members, N-WASP and WAVE, have more widespread distributions (56). WASP proteins are proline-rich scaffolding molecules and effectors of the small GTPases, Cdc42 and Rac1 (56). WASP family members bind to actin, either through a direct interaction or via profilin or Arp2/3, and so may mediate some of the effects of Cdc42 or Rac on the cytoskeleton (57). Overexpression of WASP or N-WASP in mammalian cells leads to co-localization of F-actin with the overexpressed protein, and WASP-coated beads accumulate F-actin and exhibit motility within cells (56).

A model for Shigella motility suggests that co-localization of vinculin, VASP, profilin, and N-WASP may drive actin polymerization (58). Although speculative, such co-localization may also occur in vivo via associations of Nck, PINCH, and ILK (integrin linked kinase) with integrins (Fig. 2). ILK was identified as a binding protein of the integrin ₁ and ₃ tails (59), and ankyrin repeats within ILK appear to mediate binding to the LIM domain-only protein PINCH and recruit it to integrin complexes in spreading cells (59). PINCH also interacts with Nck-2, an SH2/SH3-containing protein, and so mediates an association between Nck-2 and ILK (59). The C-terminal SH3 domain of the closely related adapter protein Nck-1 binds to WASP (56). This domain is 75% identical to the corresponding Nck-2 SH3 domain, suggesting that a protein complex containing integrin, ILK, PINCH, Nck-2, WASP, and Arp2/3 might localize actin polymerization to sites of integrin-ECM contact in the lamellipodia of migrating cells. Some support for this hypothesis comes from unc-97 mutants in Caenorhabditis elegans. The UNC-97 protein belongs to the PINCH family of LIM domain proteins and is co-localized with  integrin at dense bodies (60), where it is required for the assembly and stability of these FA-like structures (60).

In conclusion, integrins associate with the actin cytoskeleton through a number of molecular linkages. In most cells, binding of the  integrin cytoplasmic tail to talin is an early and important step and probably provides a preliminary connection, which is reinforced by subsequent binding of -actinin and vinculin. In turn, these proteins probably function to bring additional F-actin to the adhesion site, and they may also recruit zyxin, Mena/VASP, and profilin. Recruitment of WASP and Arp2/3 may lead to further actin polymerization and reorganization. The large number of actin-binding proteins within matrix adhesions and their numerous structural and functional interactions with integrins provide an important basis for the control of cellular functions by integrins.

	FOOTNOTES

^* This minireview will be reprinted in the 2000 Minireview Compendium, which will be available in December, 2000. This is the second article of four in the "Integrins Minireview Series." The authors acknowledge the support of the National Institutes of Health.

^¶ To whom correspondence should be addressed. Tel.: 858-784-7124; Fax: 858-784-7343; E-mail: ginsberg@scripps.edu.

Published, JBC Papers in Press, May 4, 2000, DOI 10.1074/jbc.R900037199

	ABBREVIATIONS

The abbreviations used are: ECM, extracellular matrix; FA, focal adhesions; ERM, ezrin, radixin, and moesin; VASP, vasodilator-stimulated phosphoprotein; WASP, Wiskott-Aldrich syndrome protein; ILK, integrin-linked kinase.

	REFERENCES

TOP INTRODUCTION Role of Integrin Cytoplasmic... Specific Integrin-Cytoskeleton... Inside-out Integrin Signaling:... Integrin-associated Proteins... REFERENCES

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