Abstract
Integrin signaling has a critical function in organizing cells in tissues during both embryonic development and tissue repair. Following their binding to the extracellular ligands, the intracellular signaling pathways triggered by integrins are directed to two major functions: organization of the actin cytoskeleton and regulation of cell behaviour including survival, differentiation and growth. Basic research conducted in the past twelve years has lead to remarkable breakthroughs in this field. Integrins are catalytically inactive and translate positional cues into biochemical signals by direct and/or functional association with intracellular adaptors, cytosolic tyrosine kinases or growth factor and cytokine receptors. The purpose of this chapter is to highlight recent experimental and conceptual advances in integrin signaling with particular emphasis on the ability of integrins to regulate Fak/Src family kinases (SFKs) activation and the cross-talk with soluble growth factors receptors and cytokines.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hynes RO. The emergence of integrins: a personal and historical perspective. Matrix Biol 2004; 23:333–40.
Sastry SK, Burridge K. Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp Cell Res 2000; 261:25–36.
Lock JG, Wehrle-Haller B, Stromblad S. Cell-matrix adhesion complexes: master control machinery of cell migration. Semin Cancer Biol 2008; 18:65–76.
Arnaout MA, Goodman SL, Xiong JP. Structure and mechanics of integrin-based cell adhesion. Curr Opin Cell Biol 2007; 19:495–507.
Garcia-Alvarez B, de Pereda JM, Calderwood DA et al. Structural determinants of integrin recognition by talin. Mol Cell 2003; 11:49–58.
Vinogradova O, Velyvis A, Velyviene A et al. A structural mechanism of integrin a(IIb)beta(3) “inside-out” activation as regulated by its cytoplasmic face. Cell 2002; 110:587–97.
Ma YQ, Qin J, Wu C et al. Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol 2008; 181:439–46.
Montanez E, Ussar S, Schifferer M et al. Kindlin-2 controls bidirectional signaling of integrins. Genes Dev 2008; 22:1325–30.
Moser M, Nieswandt B, Ussar S et al. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 2008; 14:325–30.
Brakebusch C, Fassler R. The integrin-actin connection, an eternal love affair. EMBO J 2003; 22:2324–33.
Legate KR, Montanez E, Kudlacek O et al. ILK, PINCH and parvin: the tIPP of integrin signaling. Nat Rev Mol Cell Biol 2006; 7:20–31.
Nayal A, Webb DJ, Horwitz AF. Talin: an emerging focal point of adhesion dynamics. Curr Opin Cell Biol 2004; 16:94–8.
Ziegler WH, Liddington RC, Critchley DR. The structure and regulation of vinculin. Trends Cell Biol 2006; 16:453–60.
Dike LE, Farmer SR. Cell adhesion induces expression of growth-associated genes in suspension-arrested fibroblasts. Proc Natl Acad Sci USA 1988; 85:6792–6.
Eierman DF, Johnson CE, Haskill JS. Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates. J Immunol 1989; 142:1970–6.
Defilippi P, Tarone G, Gismondi A, Santoni A, eds. Integrins and Signal Transduction. Austin/New York: Landes Bioscience/Springer, 2006.
Giancotti FG, Tarone G. Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu Rev Cell Dev Biol 2003; 19:173–206.
Miranti CK, Brugge JS. Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 2002; 4:E83–90.
Schwartz MA, Ginsberg MH. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 2002; 4:E65–8.
Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 2006; 18:516–23.
Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci 2003; 116:1409–16.
van Nimwegen MJ, van de Water B. Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol 2007; 73:597–609.
Sieg DJ, Hauck CR, Ilic D et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol 2000; 2:249–56.
Lim ST, Chen XL, Lim Y et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 2008; 29:9–22.
Yeatman TJ. A renaissance for SRC. Nat Rev Cancer 2004; 4:470–80.
Irby RB, Mao W, Coppola D et al. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 1999; 21:187–90.
Di Stefano P, Damiano L, Cabodi S et al. p140Cap protein suppresses tumour cell properties, regulating Csk and Src kinase activity. EMBO J 2007; 26:2843–55.
Moro L, Dolce L, Cabodi S 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 2002; 277:9405–14.
de Virgilio M, Kiosses WB, Shattil SJ. Proximal, selective and dynamic interactions between integrin alphaIIbbeta3 and protein tyrosine kinases in living cells. J Cell Biol 2004; 165:305–11.
Defilippi P, Di Stefano P, Cabodi S. p130Cas: a versatile scaffold in signaling networks. Trends Cell Biol 2006; 16:257–63.
Ridley AJ, Schwartz MA, Burridge K et al. Cell migration: integrating signals from front to back. Science 2003; 302:1704–9.
Webb DJ, Donais K, Whitmore LA et al. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat Cell Biol 2004; 6:154–61.
Goldberg GS, Alexander DB, Pellicena P et al. Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells. J Biol Chem 2003; 278:46533–40.
Shin NY, Dise RS, Schneider-Mergener J et al. Subsets of the major tyrosine phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration. J Biol Chem 2004; 279:38331–7.
Zhang XT, Li LY, Mu XL et al. The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced nonsmall-cell lung cancer. Ann Oncol 2005; 16:1334–42.
Burridge K, Wennerberg K. Rho and Rac take center stage. Cell 2004; 116:167–79.
Chang LC, Huang CH, Cheng CH et al. Differential effect of the focal adhesion kinase Y397F mutant on v-Src-stimulated cell invasion and tumor growth. J Biomed Sci 2005; 12:571–85.
Schwartz MA, Assoian RK. Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways. J Cell Sci 2001; 114:2553–60.
Assoian RK. Control of the G1 phase cyclin-dependent kinases by mitogenic growth factors and the extracellular matrix. Cytokine Growth Factor Rev 1997; 8:165–70.
Carrano AC, Pagano M. Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. J Cell Biol 2001; 153:1381–90.
Comoglio PM, Boccaccio C, Trusolino L. Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol 2003; 15:565–71.
Boeri Erba E, Bergatto E, Cabodi S et al. Systematic analysis of the epidermal growth factor receptor by mass spectrometry reveals stimulation-dependent multisite phosphorylation. Mol Cell Proteomics 2005; 4:1107–21.
Boeri Erba E, Matthiesen R, Bunkenborg J et al. Quantitation of multisite EGF receptor phosphorylation using mass spectrometry and a novel normalization approach. J Proteome Res 2007; 6:2768–85.
Reginato MJ, Mills KR, Paulus JK et al. Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol 2003; 5:733–40.
Monaghan-Benson E, McKeown-Longo PJ. Urokinase-type plasminogen activator receptor regulates a novel pathway of fibronectin matrix assembly requiring Src-dependent transactivation of epidermal growth factor receptor. J Biol Chem 2006; 281:9450–9.
Wang R, Ferrell LD, Faouzi S et al. Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol 2001; 153:1023–34.
Defilippi P, Rosso A, Dentelli P et al. ta1 Integrin and IL-3R coordinately regulate STAT5 activation and anchorage-dependent proliferation. J Cell Biol 2005; 168:1099–108.
Baron V, Schwartz M. Cell adhesion regulates ubiquitin-mediated degradation of the platelet-derived growth factor receptor beta. J Biol Chem 2000; 275:39318–23.
Goel HL, Fornaro M, Moro L et al. Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins. J Cell Biol 2004; 166:407–18.
Roovers K, Assoian RK. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays 2000; 22:818–26.
Aplin AE, Stewart SA, Assoian RK et al. Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol 2001; 153:273–82.
Ivankovic-Dikic I, Gronroos E, Blaukat A et al. Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2000; 2:574–81.
Eliceiri BP, Puente XS, Hood JD et al. Src-mediated coupling of focal adhesion kinase to integrin alpha(v) beta5 in vascular endothelial growth factor signaling. J Cell Biol 2002; 157:149–60.
Mariotti A, Kedeshian PA, Dans M et al. EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol 2001; 155:447–58.
Trusolino L, Bertotti A, Comoglio PM. A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 2001; 107:643–54.
Hehlgans S, Haase M, Cordes N. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta 2007; 1775:163–80.
Lahlou H, Sanguin-Gendreau V, Zuo D et al. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression. Proc Natl Acad Sci USA 2007; 104:20302–7.
White DE, Kurpios NA, Zuo D et al. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 2004; 6:159–70.
Guy CT, Muthuswamy SK, Cardiff RD et al. Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. Genes Dev 1994; 8:23–32.
Guo W, Pylayeva Y, Pepe A et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 2006; 126:489–502.
Bon G, Folgiero V, Di Carlo S et al. Involvement of alpha6beta4 integrin in the mechanisms that regulate breast cancer progression. Breast Cancer Res 2007; 9:203.
Brakebusch C, Fassler R. beta 1 integrin function in vivo: adhesion, migration and more. Cancer Metastasis Rev 2005; 24:403–11.
Christofori G. New signals from the invasive front. Nature 2006; 441:444–50.
Elliott BE, Ekblom P, Pross H et al. Anti-beta 1 integrin IgG inhibits pulmonary macrometastasis and the size of micrometastases from a murine mammary carcinoma. Cell Adhes Commun 1994; 1:319–32.
Khalili P, Arakelian A, Chen G et al. A nonRGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther 2006; 5:2271–80.
Kren A, Baeriswyl V, Lehembre F et al. Increased tumor cell dissemination and cellular senescence in the absence of beta1-integrin function. EMBO J 2007; 26:2832–42.
Serini G, Napione L, Arese M et al. Besides adhesion: new perspectives of integrin functions in angiogenesis. Cardiovasc Res 2008; 78:213–22.
Huveneers S, Truong H, Danen HJ. Integrins: signaling, disease and therapy. Int J Radiat Biol 2007; 83:743–51.
Cabodi S, Morello V, Masi A et al. Convergence of integrins and EGF receptor signaling via P13K/Akt/ FoxO pathway in early gene Egr-1 expression. J Cell Physiol. 2009; 218:294–303.
Cabodi S, Tinnirello A, Di Stefano P et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006; 1:4672–4680.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Cabodi, S. et al. (2010). Integrins and Signal Transduction. In: Becchetti, A., Arcangeli, A. (eds) Integrins and Ion Channels. Advances in Experimental Medicine and Biology, vol 674. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6066-5_5
Download citation
DOI: https://doi.org/10.1007/978-1-4419-6066-5_5
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-6065-8
Online ISBN: 978-1-4419-6066-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)