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Binding of the phosphotyrosine-binding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails ( Wegener et al., 2007). Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation ( Calderwood, 2004 Ginsberg et al., 2005 Tadokoro et al., 2003). The specifics of extracellular ligand binding and the range of known integrin ligands are reviewed elsewhere ( Humphries et al., 2006 Luo et al., 2007). We focus on integrin-proximal events because these allow us to illustrate signalling to and from integrins more easily. Furthermore, the conservation of integrin β-tails means that their interactions can be generalised more readily than those of the more diverse α-tails, and this is likely to bias the view of integrin signalling that we present. To summarise integrin signalling briefly, therefore, we must make generalisations and omit many reported interactions and pathways. Using the large literature on integrin signalling, Geiger and colleagues have recently described a network of 156 components (linked via 690 interactions) that make up the integrin `adhesome' ( Zaidel-Bar et al., 2007). Outside-in and inside-out signalling require dynamic, and spatially and temporally regulated assembly and disassembly of multiprotein complexes that form around the cytoplasmic tails of integrins.
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They do this by undergoing conformational changes in their extracellular domains that occur in response to signals that impinge upon the integrin cytoplasmic tails – a process that is termed inside-out signalling or activation ( Calderwood, 2004). In addition to outside-in signalling, integrins can regulate their affinity for extracellular ligands. These signals determine cellular responses such as migration, survival, differentiation and motility, and provide a context for responding to other inputs, including those transmitted by growth-factor- or G-protein-coupled receptors. In addition to their mechanical roles in anchorage, integrins transmit chemical signals into the cell (outside-in signalling), providing information on its location, local environment, adhesive state and surrounding matrix ( Hynes, 2002 Miranti and Brugge, 2002). These processes rely on the linkage of integrins to the intracellular cytoskeleton through the generally short integrin cytoplasmic tails such linkage permits the bi-directional transmission of force across the plasma membrane ( Calderwood et al., 2000 Evans and Calderwood, 2007).
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The specific binding of the extracellular domains of integrins to extracellular-matrix (ECM) proteins or, in some cases, to counter-receptors on adjacent cells, supports cell adhesion and is crucial for embryonic development, tissue maintenance and repair, host defence and haemostasis. They are heterodimers of noncovalently associated α and β subunits, each of which is a single-pass type I transmembrane protein ( Humphries et al., 2006 Hynes, 2002). Integrins are a major family of cell-surface-adhesion receptors that are expressed in all metazoans.