Integrin signaling: It's where the action is

Current Opinion in Cell Biology

Volumn 14, Issue 5, 2002, Pages 594-602

  Damsky, Caroline H ^a   Ili, Duško ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GROWTH FACTOR; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATE; INTEGRIN RECEPTOR; PROTEIN CDC42; PROTEIN KINASE B; PROTEIN KINASE C; RAC PROTEIN; REGULATOR PROTEIN; RHO FACTOR;

ANGIOGENESIS; ANIMAL CELL; APOPTOSIS; CELL DEATH; CELL GROWTH; CELL MEMBRANE; CELL MIGRATION; CELL NUCLEUS; CELL POLARITY; CELL STRUCTURE; CELL SURVIVAL; CELL TYPE; EXTRACELLULAR MATRIX; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; MORPHOGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN TRANSPORT; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

ANIMALIA;

EID: 0036775137     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(02)00368-X     Document Type: Review

References (87)

1. Giancotti F.G., Ruoslahti E. Integrin signaling. Science. 285:1999;1028-1032.
2. Miranti C.K., Brugge J.S. Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol. 4:2002;E83-E90. Reviews [1,2••,3-9] are excellent; Miranti and Brugge deserve special mention for their prodigious historical review of integrin signaling!
3. Schwartz M.A., Ginsberg M.H. Networks and crosstalk: integrin signaling spreads. Nat Cell Biol. 4:2002;E65-E68.
4. Webb D.J., Parsons J.T., Horwitz A.F. Adhesion assembly, disassembly and turnover in migrating cells - over and over and over again. Nat Cell Biol. 4:2002;E97-E100.
5. Aplin A.E., Juliano R.L. Regulation of nucleocytoplasmic trafficking by cell adhesion receptors and the cytoskeleton. J Cell Biol. 155:2001;187-191.
6. Howe A.K., Aplin A.E., Juliano R.L. Anchorage-dependent ERK signaling-mechanisms and consequences. Curr Opin Genet Dev. 12:2002;30-35.
7. Assoian R.K., Schwartz M.A. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation G1 phase cell-cycle progression. Curr Opin Gen Dev. 11:2001;48-53.
8. Frisch S.M., Screaton R.A. Anoikis mechanisms. Curr Opin Cell Biol. 13:2001;555-562.
9. Elicieri B., Cheresh D.A. Adhesion events in angiogenesis. Curr Opin Cell Biol. 13:2001;563-568.
10. Miyamoto S.H., Teramoto H., Gutkind J.S., Yamada K.M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 135:1996;1633-1642.
11. Sieg D.J., Hauck C.R., Ilić D., Klingbeil C.K., Schaefer E., Damsky C.H., Schlaepfer D.D. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2:2000;249-256. This study provides evidence of a direct interaction between focal adhesion kinase (FAK) and growth factor receptors (GFRs) in fibroblastic cells. This suggests that FAK can act as a scaffold that bridges cytoplasmic domains of GFRs and either integrins or proteins that interact directly with integrin cytoplasmic domains.
12. Ivanković-Dikić I., Gronroos E., Blaukat A., Barth B.U., Dikić I. Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol. 2:2000;574-581.
13. 2 tail suppress activation of p38 MAPK and migration in response to epidermal growth factor and activation of ERK and cell cycle progression in response to insulin. These data provide further evidence of the intricacy of the relationships between integrins and growth factors.
14. Renshaw M.W., Price L.S., Schwartz M.A. Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase. J Cell Biol. 147:1999;611-618.
15. Barberis L., Wary K.K., Fiucci F., Liu F., Hirsch E., Brancaccio M., Altruda F., Tarone G., Giancotti F.G. Distinct roles of the adaptor protein Shc and focal adhesion kinase in integrin signaling to ERK. J Biol Chem. 275:2000;36532-36540.
16. CIP1 via cdc42/Rac1 signaling. Mol Cell Biol. 22:2002;4587-4597.
17. Howe A.K., Juliano R.L. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase. Nat Cell Biol. 2:2000;593-600.
18. Mettouchi A., Klein S., Guo W., Lopez-Lago M., Lemichez E., Westwick J.K., Giancotti F.G. Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mol Cell. 8:2001;115-127.
19. Welsh C.F., Roovers K., Villanueva J., Liu Y.Q., Schwartz M.A., Assoian R.K. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nat Cell Biol. 3:2001;950-957. This paper suggests even greater complexity in the regulation of cyclin D1 expression, by showing different kinetics of regulation by different Rho GTPases.
20. Aplin A.E., Stewart S.A., Assoian R.K., Juliano R.L. Integrin-mediated adhesion Regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol. 153:2001;273-282. The authors show that integrin regulation of ERK extends beyond its sustained expression to include its nuclear translocalization and transcription factor phosphorylation.
21. Del Pozo M.A., Price L.S., Alderson N.B., Ren X.D., Schwartz M.A. Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector Pak. EMBO J. 19:2000;2008-2014.
22. Del Pozo M.A., Kiosses W.B., Alderson N.B., Meller N., Hahn K.M., Schwartz M.A. Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. Nat Cell Biol. 4:2002;232-239. This work builds on data from Del Pozo et al. (2000) [21] and uses fluorescence resonance energy transfer, along with other methods, to show that integrins promote the dissociation of GDP dissociation inhibitor (GDI) from GTP-loaded Rac at specific membrane sites, allowing the latter's highly localized interactions with its effector.
23. Chicurel M.E., Singer R.H., Meyer C.J., Ingber D.E. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature. 392:1998;730-733.
24. Wang R., Ferrell L.D., Faouzi S., Maher J.J., Bishop J.M. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol. 153:2001;1023-1034. This study makes use of the tetracycline-sensitive transgene expression system to show that overexpression of human c-Met (which cannot interact with mouse hepatocyte growth factor [HGF] ligand) in hepatocytes is sufficient to induce and sustain hepatocellular carcinoma. Tumor progression can be turned off by adding the tetracycline derivative doxycycline and accelerated by withdrawing doxycycline. These studies are complemented by in vitro documentation of the ability of adhesion alone to activate c-Met in the absence of human HGF when c-Met is expressed at high levels.
25. Moro L., Dolce L., Cabodi E., Bergatto, Erba E.B., Smeriglio M., Turco E., Retta S.F., Giuffrida M.G., Venturino M., et al. Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem. 277:2002;9405-9414. This study builds on previous work showing that epidermal growth factor (EGF) receptor can be activated by adhesion in the absence of ligand, by documenting components of the pathway downstream of integrin-mediated adhesion. Most interesting is the evidence that the pattern of EGF receptor phosphorylation triggered by adhesion is distinct from that promoted by EGF.
26. Yamada K.M., Even-Ram S. Integrin regulation of growth factor receptors. Nat Cell Biol. 4:2002;E75-E76.
27. Pece S., Gutkind J.S. Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J Biol Chem. 275:2000;41227-41233.
28. Williams E.J., Williams G., Howell F.V., Skaper S.D., Walsh F.S., Doherty P. Identification of an N-cadherin motif that can interact with the fibroblast growth factor receptor and is required for axonal growth. J Biol Chem. 276:2001;43879-43886.
29. 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 96:1999;319-328.
30. 1 can be activated by integrin: in this case MT1 matrix metalloproteinase is also involved, underscoring the close interrelationship of growth factors and proteinases at sites of cell adhesion.
31. Fincham V.J., James M., Frame M.C., Winder S.J. Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesions by integrin engagement and v-Src. EMBO J. 19:2000;2911-2923.
32. Levkau B., Herren B., Koyama H., Ross R., Raines E.W. Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis. J Exp Med. 187:1998;579-586.
33. Nix D.A., Fradelizi J., Bockholt S., Menichi B., Louvard D., Friederich E., Beckerle M.C. Targeting of zyxin to sites of actin membrane interaction and to the nucleus. J Biol Chem. 276:2001;34759-34767.
34. Nakamoto T., Yamagata T., Sakai R., Ogawa S., Honda H., Ueno H., Hirano N., Yazaki Y., Hirai H. CIZ, a zinc finger protein that interacts with p130(Cas) and activates the expression of matrix metalloproteinases. Mol Cell Biol. 20:2000;1649-1658.
35. 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J Cell Biol. 129:1995;867-879.
36. Kheradmand F., Werner E., Tremble P., Symons M., Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science. 280:1998;898-902.
37. Lin S.Y., Makino K., Xia W., Matin A., Wen Y., Kwong K.Y., Bourguignon L., Hung M.C. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 3:2001;802-808.
38. Kraynov V.S., Chamberlain C., Bokoch G.M., Schwartz M.A., Slabaugh S., Hahn K.M. Localized Rac activation dynamics visualized in living cells. Science. 290:2000;333-337.
39. Etienne-Manneville S., Hall A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ Cell. 106:2000;489-498. A careful analysis of very early events following 'wounding' of an astrocyte monolayer shows that an initial signal from integrins to cdc42 regulates the direction of orientation of the microtubule organizing center, such that extensions are projected in the appropriate direction for efficient closure. Interestingly, it is the microtubule component of the cytoskeleton that is the target of this integrin-cdc42 signal.
40. O'Brien L.E., Jou T.S., Pollack A.L., Zhang Q., Hansen S.H., Yurchenco P., Mostov K.E. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. 3:2001;831-838.
41. 5 integrin, paxillin, and α-actinin during formation and disassembly of adhesions in migrating cells. J Cell Biol. 153:2001;1427-1440. This paper describes the effective use of green fluorescent protein and related tags to express and follow the dynamics of integrins and cytoskeletal components as cells form new adhesions and retract old ones during migration. The very different dynamics of paxillin and α-actinin is a surprise and shows the power of this approach to dissect, in an unbiased manner, how different molecules behave as adhesion sites form and mature.
42. Ridley A.J. Rho family proteins: coordinating cell responses. Trends Cell Biol. 11:2001;471-477.
43. 2-terminal kinase. J Cell Biol. 149:2000;741-754. This paper demonstrates the formation of a focal adhesion kinase (FAK) - p130Cas signaling complex that includes activated c-Jun amino-terminal kinase at focal adhesion sites in serum-deprived fibroblasts plated on fibronectin, which supports survival, but not on collagen, which does not. This survival pathway is initiated by adhesion on a two-dimensional matrix in the absence of serum, in contrast to a phosphatidylinositol 3-kinase/AKT regulated pathway that supports survival in fibroblasts when serum is present but an appropriate matrix is not (see also Tian et al. (2002) [46•] ).
44. Ilić D., Almeida E.A.C., Schlaepfer D.D., Dazin P., Aizawa S., Damsky C.H. Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J Cell Biol. 143:1998;547-560.
45. Khwaja A., Rodriguez-Viciana P., Wennstrom S., Warne P.H., Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16:1997;2783-2793.
46. 1 integrin can sustain activation of phosphatidylinositol 3-kinase and cell survival throughout the gel contraction process, which progressively releases tension on integrins and the cytoskeleton and is usually associated with apoptosis.
47. Gilmore A.P., Metcalfe A.D., Romer L.H., Streuli C.H. Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J Cell Biol. 149:2000;431-446.
48. Aoudjit F., Vuori K. Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-Flip and implications for anoikis. J Cell Biol. 152:2001;633-643. This interesting study describes a novel mechanism by which Fas-mediated cell death is suppressed in endothelial cells by matrix adhesion. Matrix attachment both suppresses Fas expression and stimulates expression of c-Flip, a suppressor of caspase-8.
49. V integrins might function in developmental and pathologic angiogenesis in vivo.
50. 1 fibronectin receptor. J Cell Biol. 150:2000;1467-1478.
51. Prince J.M., Klinowska T.C., Marshman E., Lowe E.T., Mayer U., Miner J., Aberdam D., Vestweber D., Gusterson B., Streuli C.H. Cell-matrix interactions during development and apoptosis of the mouse mammary gland in vivo. Dev Dyn. 223:2002;497-516.
52. Zhong C., Chrzanowska-Wodnicka M., Brown J., Shaub A., Belkin A.M., Burridge K. Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J Cell Biol. 141:1998;539-551.
53. Sechler J.L., Rao H., Cumiskey A.M., Vega-Colon I., Smith M.S., Murata T., Schwarzbauer J.E. A novel fibronectin binding site required for fibronectin fibril growth during matrix assembly. J Cell Biol. 154:2001;1081-1088.
54. Wierzbicka-Patynowski I., Schwarzbauer J. Regulatory role for Src and PI3-kinase in initiation of fibronectin matrix assembly. J Biol Chem. 277:2002;19703-19708.
55. 1 integrins promotes early fibronectin fibrillogenesis. J Cell Biol. 148:2000;1075-1090. An elegant study showing how initial focal adhesion sites are remodeled as cells spread on a planar substratum. This remodeling is shown to be closely coupled to assembly of a fibrillar matrix. Notably, the molecular composition of initial focal adhesion sites and the remodeled 'fibrillar adhesions' are distinct. This study was followed by one that analyses adhesions formed in three-dimensional matrices (see the review by Cukierman et al., pp 633-639).
56. Furuta Y., Ilić D., Kanazawa S., Takeda N., Yamamoto T., Aizawa S. Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene. 11:1995;1989-1995.
57. George E.L., Baldwin H.S., Hynes R.O. Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells. Blood. 90:1997;3073-3078.
58. Kovaćić-Milivojević B., Roediger F., Almeida E.A.C., Damsky C.H., Gardner D.G., Ilić D. Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy. Mol Biol Cell. 12:2001;2290-2307. This study reveals striking parallels in molecular composition of focal contact sites in fibroblasts and Z-lines in cardiomyocytes, suggesting that the latter are important signaling centers. In support of this idea, expression of dominant-negative fragments of focal adhesion kinase (FAK) in neonatal cardiomyocytes disrupts both cytoarchitecture and tissue-specific gene expression.
59. Parast M.M., Otey C. Characterization of palladin, a novel protein localized to stress fibers and cell adhesions. J Cell Biol. 150:2000;643-656.
60. Brugge J.S. Casting light on focal adhesions. Nat Genet. 19:1998;309-311.
61. Turner C.E., West K.A., Brown M.C. Paxillin-ARF GAP signaling and the cytoskeleton. Curr Opin Cell Biol. 13:2001;593-599.
62. Honda H., Oda H., Nakamoto T., Honda Z., Sakai R., Suzuki T., Saito T., Nakamura K., Nakao K., Ishikawa T., et al. Cardiovascular anomaly, impaired actin bundling and resistance to Src-induced transformation in mice lacking p130Cas. Nat Genet. 19:1998;361-365.
63. Hagel M., George E.L., Kim A., Tamimi R., Opitz S.L., Turner C.E., Imamoto A., Thomas S.M. The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol Cell Biol. 22:2002;901-915.
64. V integrins as a mechanism to create surplus, unligated integrins, thereby inducing apoptosis (see also Stupack et al. [2001] [49•]).
65. Diaz-Gonzalez F., Forsyth J., Steiner B., Ginsberg M.H. Trans-dominant inhibition of integrin function. Mol Biol Cell. 7:1996;1939-1951.
66. Woods A., Couchman J.R. Syndecan-4 and focal adhesion function. Curr Opin Cell Biol. 13:2001;578-583.
67. Woods A. Syndecans: transmembrane modulators of adhesion and matrix assembly. J Clin Invest. 107:2001;935-941.
68. Hemler M.E. Specific tetraspanin functions. J Cell Biol. 155:2001;1103-1107.
69. Denker S.P., Huang D.C., Orlowski J., Furthmayr H., Barber D.L. Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Mol Cell. 6:2000;1425-1436.
70. Denker S.P., Barber D.L. Ion transport proteins anchor and regulate the cytoskeleton. Curr Opin Cell Biol. 14:2002;214-220.
71. Stadler H.S., Higgins K.M., Capecchi M.R. Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Development. 128:2001;4177-4188. This study describes the defects in cell-matrix and cell-cell adhesion of limb mesenchymal cells from Hoxa13-null mice. Expression of integrins and cadherins is not affected even though adhesiveness of the cells is greatly reduced. However, specific Eph/ephrin partner(s) are absent or mislocalized. Proximal and distal compartment boundaries in the limb are not formed and the chondrogenic gene program is not turned on. The study implies a hierarchy of regulation from Hox genes, to Eph/ephrins, to the regulation of adhesion receptor function. If true, this would provide new insight into how instructions from transcription factors might affect adhesion receptors - currently a huge blank in our understanding of upstream regulation of adhesion receptor function.
72. Wilkinson D.G. Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci. 2:2001;155-164. The most recent of several reviews by this author of the structure, function and roles of these large families of membrane-associated ligands and receptors in regulating compartment boundaries and pathfinding during development. The emphasis is on neuronal cells, but the concepts are applicable to the vascular system and other tissues throughout the embryo where these modifiers of cell adhesion are expressed. Determining how they affect the functions of integrins (and cadherins as well) is a fascinating undertaking - and the field is still wide open!
73. Miao H., Burnett E., Kinch M., Simon E., Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2:2000;62-69.
74. Zou J.X., Wang B., Kalo M.S., Zisch A.H., Pasquale E.B., Ruoslahti E. An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci USA. 96:1999;13813-13818.
75. Cowan C.A., Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature. 413:2001;174-179.
76. Wahl S., Barth H., Ciossek T., Aktories K., Mueller B.K. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J Cell Biol. 149:2000;263-270.
77. Shamah S.M., Lin M.Z., Goldberg J.L., Estrach S., Sahin M., Hu L., Bazalakova M., Neve R.L., Corfas G., Debant A., Greenberg M.E. EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell. 105:2001;233-244.
78. Huai J., Drescher U. An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein. J Biol Chem. 276:2001;6689-6694.
79. Holmberg J., Clarke D.L., Frisen J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature. 408:2000;203-206.
80. Calderwood D.A., Yan B., de Pereda J.M., Garcia-Alvarez B., Fujioka Y., Liddington R.C., Ginsberg M.H. The phosphotyrosine binding (PTB)-like domain of talin activates integrins. J Biol Chem. 277:2002;21749-21758. This paper dissects the structural basis of the activation of integrins by talin. It illustrates nicely how recent advances in our understanding of protein structural motifs shed light on how proteins such as talin, which interacts directly with tails of integrin β subunits, can switch integrins on.
81. 4 cytoplasmic domain regulates paxillin binding. J Biol Chem. 276:2001;40903-40909.
82. Liu S., Calderwood D.A., Ginsberg M.H. Integrin cytoplasmic domain-binding proteins. J Cell Sci. 113:2000;3563-3571.
83. Martin-Bermudo M.D. Integrins modulate the EGFR signaling pathway to regulate tendon cell differentiation in the Drosophila embryo. Development. 127:2000;2607-2615.
84. Roy P., Rajfur Z., Pomorski P., Jacobson K. Microscope-based techniques to study cell adhesion and migration. Nat Cell Biol. 4:2002;E91-E96.
85. Bell S.E., Mavila A., Salazar R., Bayless K.J., Kanagala S., Maxwell S.A., Davis G.E. Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci. 114:2001;2755-2773.
86. Clark E.A., Golub T.R., Lander E.S., Hynes R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 406:2000;532-535.
87. Ilić D., Genbacev O., Jin F., Caceres E., Almeida E.A.C., Bellingard-Dubouchaud V., Damsky C.H., Fisher S.J. Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am J Pathol. 159:2001;93-108.