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466 Review TRENDS in Biology Vol.11 No.12 December 2001 signaling revisited

Martin A. Schwartz

Adhesion to the (ECM) is a crucial regulator of cell function, appear to be downstream of FAK and to contribute to and it is now well established that signaling by mediates many of cell migration12,13. The adaptor protein p130cas also these effects. Ten years of research has seen integrin signaling advance on binds to FAK and has been linked to activation of the many fronts towards a molecular understanding of the control mechanisms. small GTPase Rac to promote motility. This diversity of Most striking is the merger with studies of other receptors, the downstream pathways that converge on and mechanical forces within the general field of signaling networks. suggests that FAK is a central coordinator of this process. FAK has also been implicated in cell-cycle When I wrote a Trends in Cell Biology review on regulation through activation of both the Erk and integrin signaling in 19921, a 3000-word article could JNK pathways. And FAK plays an important role in cover the entire subject without omitting any key mediating integrin-dependent cell survival, possibly references. In the year 2000 alone, a literature search through phosphoinositide (PI) 3- or JNK7,8,14,15. on ‘integrin’ plus ‘’ yielded 480 Multiple physical associations of FAK with references. Given the impossibility of covering more other signaling molecules appear to mediate these than a sliver of what’s been written, I have chosen to multiple effector pathways. Proteins that bind to revisit the topics discussed in 1992, several of which autophosphorylated FAK through their Src-homology seem to have developed in interesting ways. 2 (SH2) domains include c-Src family , GRB7 A good deal of this expansion has been lateral. Even (Ref. 16), phospholipase Cγ1 (Ref. 17) and PI 3-kinase. beyond my fairly wild dreams, integrins and integrin p130cas and a GTPase-activating protein (GAP) for Rho signaling have found their way into nearly every named GRAF bind to proline-rich sequences in the C- biological process. Integrin signals evidently play terminus of FAK through their Src-homology 3 (SH3) important roles in transplantation, , viral domains. , and STAT1 bind through and bacterial infections, immune recognition, sequences near the C-terminus. The Etk tyrosine development, atherogenesis and nearly every other kinase directly binds to sequences in the N-terminus, complex physiological or pathological process in and the PDGF also associates (although vertebrate organisms2–4. Luckily, I feel no obligation to perhaps indirectly) with the N-terminal region. Many review this vast literature. However, a second kind of of the proteins phosphorylated downstream of FAK expansion still complicates the task. Integrin signaling might actually be substrates of associated Src-family has undergone a remarkable merger with other areas kinases. Indeed, it has been suggested that FAK is best of signaling, particularly those involving the regarded as an adaptor protein with kinase activity7. cytoskeleton and / receptors5,6. Clearly, FAK promotes assembly of signaling This trend in cell biology reflects the general paradigm complexes downstream of integrins that lead to a wide shift towards understanding signal transduction in range of events; however, the detailed mechanisms by terms of spatially organized complex networks. which particular partners induce specific downstream events are not well understood. An overview of what is Tyrosine kinases known is presented in Fig. 1. In 1992, kinase (FAK) had just been The Src tyrosine kinases, in addition to their role identified as a protein tyrosine kinase activated by as cofactors for FAK-dependent responses, can be integrin-mediated adhesion and localized to sites of activated independently of FAK and contribute to a adhesion. FAK has since emerged as a remarkably distinct set of responses. Src tyrosine kinases mediate complex and interesting molecule. The reader is also phosphorylation of the adaptor Shc, which provides a directed to earlier reviews that cover FAK biochemistry separate link to the Ras/Erk pathway (reviewed in in greater detail7,8. FAK is essential for multicellular Ref. 18). They also phosphorylate Jab-1, which is a life, as, in its absence, mice die early during component of the nuclear signalosome that regulates embryogenesis. Even cells isolated from FAK–/– the proteasome-dependent degradation of a number embryos show severe defects in cytoskeletal of nuclear proteins19; this pathway also contributes to organization and motility. These defects appear to be integrin regulation of c-Fos. due to a surprising number of molecular mechanisms. Other tyrosine kinases regulated by integrins Martin A. Schwartz –/– Dept of Vascular Biology, FAK cells show abnormal regulation of the small include syk, c-Abl and receptor tyrosine kinases such 9 Scripps Research GTPase Rho , of the mitogen-activated protein kinase as the epidermal (EGFR) and Institute, 10550 North (MAPK) Erk10 and abnormal signaling through the c-Met. Activation of syk is a very early event following Torrey Pines Road, -derived growth factor (PDGF) receptor11. stimulation of the integrin αIIbβ3 in or β2 La Jolla, CA 92037, USA. e-mail: Additional mechanisms involve the Etk tyrosine kinase integrins on leukocytes (reviewed in Ref. 20). Unlike [email protected] and the Stat1, both of which FAK, syk activation does not depend on the actin

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Fig. 1. Focal adhesion stimulation do not show a tight correlation between kinase (FAK). FAK has FERM Kinase FAT their GTP loading and PIP 5-kinase activity29,30. This multiple binding partners, Y397 discrepancy might be resolved by recent work many of which appear to PR PR Y925 function as downstream showing that integrins regulate GTPase function at a PDGFR Etk effectors. A large number PI 3-K Src Grb7 Talin second step – that of membrane translocation. Rac in of these proteins, CAS GRAF Grb2 Paxillin non-adherent cells could undergo GTP loading but including the platelet- Stat1 derived growth factor failed to interact with effectors because it failed to receptor (PDGFR), Etk, Rac Rho Ras associate with membranes30. Rho and Cdc42 phosphoinositide (PI) evidently behave similarly (M. del Pozo and 3-kinase, Grb7, p130cas (CAS), GRAF, Stat1 and M. Schwartz, unpublished). This effect appears to Survival Migration Growth Erk appear to contribute account for nearly complete shut-off of Rac pathways to cell migration. TRENDS in Cell Biology in non-adherent cells. As membrane translocation Additionally, FAK can should be crucial for PIP 5-kinase to interact with its contribute to and survival, most likely substrate, this effect might account for a significant through pathways that cytoskeleton. The Syk kinase contributes to integrin- portion of the regulation of PIP2 synthesis by regulate Erk, JNK and mediated gene expression in and to the integrins, which could involve both Rho and Rac. As PI 3-kinase. FAK domains include the N-terminal spreading of platelets. This last effect is most likely PIP2 is also a key regulator of the actin cytoskeleton, a FERM (band 4.1, ezrin, due to phosphorylation by syk of the Rac nucleotide substrate for phosphoinositide 3-kinase and a binding radixin and moesin) exchange factor Vav1 (Ref. 21). c-Abl contributes to the site for some pleckstrin-homology domains31, domain and a FAT (focal integrin activation of Erk (Ref. 22) and serves to inhibit integrin-dependent changes in PIP levels or adhesion targeting) 2 sequence. cell migration through an inhibitory phosphorylation synthesis could have pleiotropic effects on cell of the SH2/SH3 domain adaptor protein c-Crk, leading signaling and membrane–protein interactions. to decreased assembly of a complex between Crk and p130cas and decreased activation of Rac (Ref. 23). Proximal signals Integrins also induce transactivation of c-met and The proximal mechanisms by which integrins signal EGFR tyrosine kinase growth factor receptors in the constitute crucially important unknowns to which we absence of their growth factor ligands24,25. This process have little insight. Lacking enzymatic activity, appears to be crucially dependent on the level of integrins must associate with other proteins, essentially growth factor receptor, being apparent only at high adaptors, to trigger signals. The major area of levels of expression. Transactivation of these receptors progress has been the identification of such adaptors. contributes to integrin activation of the Ras–Erk Integrin cytoplasmic domains bind directly to pathway24 and to tumorigenesis25. several cytoskeletal proteins that might associate with signaling molecules (reviewed in Ref. 32). For Phosphoinositides example, the β1A, β3 and β1D cytoplasmic domains The 1992 review described work from my laboratory bind to talin; the β1A tail binds to α-; β1A, β2 that revealed how integrins could modulate the and β7 tails bind to filamin; and the α4 tail binds to ability of growth factors to stimulate paxillin. Filamin and paxillin are excellent phosphoinositide turnover. We found that candidates for mediating signaling effects as they

phosphatidylinositol (4,5)-bisphosphate (PIP2) levels associate with many other adaptor and signaling declined in nonadherent cells and that phospholipase molecules (reviewed in Refs 33 and 34). A C could still be activated by growth factors but to little serine/threonine integrin-linked kinase (ILK) was effect in the absence of its substrate (reviewed in also reported to bind to the β1A integrin cytoplasmic Ref. 26). We subsequently reported that the small domain (reviewed in Ref. 32) and to localize to focal GTPase Rho could activate the phosphatidylinositol adhesions35. This protein was proposed to function as 4-phosphate 5-kinase (PIP 5-kinase) responsible for a regulator of anchorage-dependent growth. ILK is

synthesis of PIP2. Rho also bound directly to the PIP evidently an important protein as its mutation results 5-kinase, although this binding did not require GTP in a severe phenotype in Drosophila, where the loading of Rho and did not increase the enzymatic cytoskeleton detaches from the integrins in several activity of the PIP 5-kinase. Carpenter and coworkers tissues36. However, more recent work has cast some reported that Rac bound PIP 5-kinase in a similar doubt upon whether the direct binding of ILK to manner and that, despite the absence of direct integrins mediates its localization to focal contacts or stimulation of enzymatic activity, this interaction is necessary for its function36,37.

stimulates PIP2 synthesis in activated platelets and Integrin cytoplasmic domains also bind directly to subsequent actin polymerization27. tyrosine kinases. FAK was reported to bind to The role of Rho in regulating PIP 5-kinase remained from the integrin β1 subunit (reviewed in puzzling and somewhat controversial. A recent paper Refs 7 and 8). This binding, however, involves the showed that Rho kinase played a key role in PIP N-terminus of FAK rather than the C-terminal 5-kinase activation, thereby providing a link between domain that targets it to focal adhesions and has been GTP loading and stimulation28. However, analyses of controversial. Recently, good evidence has been Rho and Rac activation in response to integrin obtained that FAK binds directly to the β5 cytoplasmic

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Fig. 2. Bidirectional Interestingly, integrin transmembrane and signaling. For inactive extracellular domains also associate with other integrins, the extracellular domain has a low affinity membrane proteins that might serve as adaptors to for extracellular matrix promote signaling. The first such interaction (ECM) ligands, while the α identified was between integrin β3 and integrin- β and cytoplasmic 2 domains associate with Ligand associated protein (IAP or CD47) . Binding is each other to induce a low mediated by the extracellular portion of the integrin affinity for intracellular β α β α to the Ig domain of CD47 and leads to formation of a cytoskeletal and signaling signaling complex containing heterotrimeric G binding partners. i Activated or occupied proteins, cholesterol and, most likely, other 44,45 integrins have a high Inactive Active components . Depletion of cholesterol dissociates affinity for ECM ligands IAP and integrins, suggesting that transmembrane outside the cell, while domains might participate. Integrin α2β1 also disruption of the intramolecular tail associates with IAP and, in all cases, IAP-dependent interactions increases the signals modulate integrin function as well as affinity for intracellular initiating other G -dependent events46. components. Intracellular i and extracellular events Integrins associate with tetraspanin proteins, a are therefore coupled family of small membrane proteins with four through cooperative transmembrane domains (‘TM4’; reviewed in Ref. 47). effects on conformation. Cytoplasmic α α binding partners Integrins 3 and 6 form a tight complex with CD151, whereas α3, α6 and αvβ3 form weaker TRENDS in Cell Biology associations with CD9, CD63 and CD81. The high-affinity interaction of CD151 with integrin α3β1 involves the extracellular regions48. Associations domain following FAK phosphorylation, which is between other tetraspanins and integrins are highly crucial for β5-mediated cell migration38. The tyrosine sensitive to even nonionic detergents such as Triton kinase syk binds directly to the β3 cytoplasmic X-100 (Ref. 45), again suggesting that domain39. Syk is activated following ligation of β3 transmembrane domains might be involved. integrins; this event is very rapid and, as discussed TM4 protein cytoplasmic domains can associate with above, has characteristics suggestive of a relatively signaling proteins such as protein kinase C (Ref. 49), direct event20,21. Clustering and occupancy of this supporting a possible adaptor function. The integrin might therefore directly induce syk activation. immediate signaling events triggered by tetraspanins Although the implications for signaling are still are unknown, but the downstream consequences hypothetical, recent structural studies have provided include modulation of cell migration and the intriguing insights. The ligand-binding domains of cytoskeleton50. integrins are globular regions near the N-termini of A distinct subset of integrins consisting of αv, α5 the α and β subunits and are connected to the and α1 associate with caveolin18. This interaction has transmembrane domains by long stalks40. Structural been mapped to the integrin transmembrane and studies have revealed large conformational changes extracellular regions. The association is sensitive to in the ligand-binding domains upon association with cholesterol depletion, suggesting that ligands41,42. Evidence suggests that these might be transmembrane domains are involved. Given the conveyed to the cytoplasmic domains by a change in participation of extracellular regions of the integrin, separation between the α and β subunits within the this association might be indirect as does not stalk region40. These studies mesh nicely with extend outside the cell. The interaction is functionally evidence that an intramolecular interaction between important as it is linked to phosphorylation of shc by the α and β cytoplasmic tails can regulate the affinity Src-family kinases, activation of the Ras–Erk of the extracellular domain for ligand43. The emerging pathway, cell proliferation and survival. Caveolin picture is therefore that separation between the C- again enters the picture through an association termini of the two subunits conveys a bidirectional between integrins and the urokinase plasminogen between the ligand-binding activator receptor (uPAR), a GPI-linked protein that domain and the cytoplasmic domain. Binding of ECM localizes to lipid rafts and caveolae51. Association of proteins to the N-terminal domains might cause a both β1 and β2 integrins with uPAR promotes the change in conformation to free the β tail from an ligand binding function of the integrins, possibly by association with the α tail that sterically blocks bringing them into proximity with other raft/caveolae interactions or constrains its conformation, thereby components. This lateral interaction is again promoting binding to intracellular signaling proteins. sensitive to depletion of cholesterol. These results are Changes in the disposition of the cytoplasmic tails summarized in Fig. 3. could similarly alter the conformation of the ligand- To briefly summarize, it appears that the most binding regions, leading to changes in affinity for central signaling events shared by all or nearly all ECM proteins. These ideas are summarized in Fig. 2. integrins originate in the β cytoplasmic domains,

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Fig. 3. Integrin binding These effects are mediated by pathways involving partners. Integrins Rho family GTPases and phosphoinositides as well as associate with other β α membrane proteins, through actin-binding proteins such as , talin, including integrin- uPAR α-actinin and actopaxin that physically link integrins associated protein (IAP), IAP to actin filaments32,54. Simultaneously, integrin signals urokinase plasminogen TM4 activator receptor (uPAR) such as FAK activation are dependent on the state of 7,8 and tetraspanin (TM4) the actin cytoskeleton . Thus, the actin cytoskeleton proteins. These Caveolin is both upstream and downstream of integrin associations occur α-actinin signaling. While growth factor/cytokine receptors are through extracellular and, Paxillin Filamin not entirely independent of actin, they do not perhaps, transmembrane ILK Talin Syk regions of the molecules. TRENDS in Cell Biology participate in the same sort of intimate relationship. Integrins also associate One consequence of this relationship is with the intramembrane . Physical stresses from outside and cytoplasmic protein caveolin – although it is whereas α subunit and lateral associations mediate the cell can be transmitted to the cytoskeleton through not clear that this signaling and modulatory functions specific to one or integrins and modify cytoskeletal organization and association is direct. The a few integrin subunits. The past decade has seen the influence signaling, and vice versa. For example, cells integrin cytoplasmic domains bind to a variety identification of many molecular interactions can the degree of mechanical resistance in the of cytoskeletal and between integrins and other molecules, but there has surrounding matrix and regulate contractility, signaling molecules, of been limited progress towards the important goal of protrusive activity, cell migration, differentiation and which only those understanding how integrin binding to the ECM growth55–58. Conversely, cells generate forces that discussed in the text are 59 shown. Abbreviation: ILK, triggers signaling. However, with so many physical regulate their own cytoskeleton and are transmitted integrin-linked kinase. protein interactions in hand, elucidating these to the ECM, where they modulate its assembly60. mechanisms now seems within reach. Assembly of cytoskeletal structures has been implicated in the ability of integrins to enhance transmission of Signaling networks growth factor signals61,62. Integrins, so named because The past ten years has seen our view of signaling they physically integrate the cytoskeleton with the pathways evolve into an understanding that they are ECM, might in fact mediate functional integration on organized into complex networks52. Signaling a much larger scale, enabling cells to modulate their pathways branch, as illustrated by the many events behavior based on their state of adhesion, mechanical downstream of FAK, and converge, as illustrated by forces and the concentrations of soluble growth factors. the many upstream pathways that can regulate PI 5- kinase, Rac or Erk. These networks allow cells to Perspectives respond in a coherent fashion to multiple stimuli. A recurring image from the past decade is the complex Signals from integrins act upon the same pathways as of cytoskeleton and signaling proteins assembled at receptors for growth factors, and antigens, sites of integrin–ECM adhesion (see Fig. 1 in Ref. 1). but often do so at different steps so that the net The general concept that integrin-dependent response is synergistic. The inositol lipid pathway assemblies guide and organize signaling is now discussed in the 1992 Trends in Cell Biology review prevalent. But, despite its appeal, the real evidence is was the first such synergy identified between thin. Clearly, immunofluorescence has shown that integrins and growth factor receptors, but it has since focal adhesions contain a variety of signaling been joined by many others. Activation of Erk, JNK, molecules. Signaling assays have shown that p38, Rac, Rho, Cdc42, PI 3-kinase, NF-κB and detaching cells from the ECM results in diminished JAK–STAT pathways by soluble factors are all transmission of many signals initiated by growth heavily influenced by integrin binding5,6. Conversely, factor/cytokine receptors. Immunoprecipitation plating cells on ECM proteins induces a transient assays indicate that most proteins are found in transactivation of growth factor receptor tyrosine multimolecular complexes. But the real workings of kinases24,25, while stimulation of growth factor these intracellular assemblies and how they transmit receptors can activate integrins to initiate new ECM and modulate signals remain very poorly understood. binding53. I do not know of any pathways that are I suggest that the elucidation of localized events Acknowledgements dedicated to only one or the other. that are spatially and temporally determined by large The writing of this review Growth factors and integrins both induce protein complexes represents the major challenge for was supported by grants from the US Public Health assembly of multicomponent complexes containing the next decade. Tackling this problem will require Service. I thank Bette kinases, adaptors, substrates and scaffolding sophisticated imaging and biochemical methods to Cessna for secretarial proteins52. This trend has gone so far that one might reveal their structure and function within living cells. assistance, my colleagues for permitting question whether integrins and growth factor Two previously unrelated fields – adhesion/cytoskeleton unpublished work to be receptors are equivalent. I suggest that integrin and signal transduction – have grown markedly closer cited and apologize to signaling is different because of its intimate in the past decade; it is now apparent that they many authors whose association with the actin cytoskeleton. Integrins represent two sides of a single coin and that a closely primary papers could not be cited owing to space induce assembly of actin filaments and higher-order integrated approach is needed to solve both problems. limitations. structures such as stress fibers and focal adhesions. Sounds like fun.

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