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Cancer Surv. 1995;24:81-96.

Convergent signalling in the action of integrins, neuropeptides, growth factors and oncogenes.

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  • 1Growth Regulation Laboratory, Imperial Cancer Research Fund, London.


These findings have important implications for signal transduction and cell regulation. Most obviously, they suggest that tyrosine phosphorylation of a novel type of tyrosine kinase p125FAK is a point of convergence in the action of integrins, oncogenic forms of pp60src, mitogenic neuropeptides and growth factors (Fig. 3). One inference is that the signal transduction pathways initiated by these diverse groups of molecules have, at least in part, similar consequences for cellular function. The notion of convergence is reinforced by the striking similarity in the overall pattern of tyrosine phosphorylation produced through these different pathways. It is tempting to speculate that p125FAK, paxillin and p130 are components in a common programme of phosphorylation events stimulated by integrins, mitogenic neuropeptides and growth factors. The localization of p125FAK to focal adhesions is clearly consistent with a role for this protein as a junction point in the transduction of signals that regulate cell substrate adhesion and ultimately cell motility and cell shape, as suggested in Fig. 3. The existence of distinct pathways leading to p125FAK phosphorylation raises the possibility of synergistic interactions between integrins and G protein coupled receptors. In fact, integrin mediated p125FAK tyrosine phosphorylation appears to be mediated by a PKC dependent pathway (Vuori and Ruoslathi, 1993). By contrast, bombesin and LPA induce tyrosine phosphorylation of p125FAK and paxillin through a PKC independent pathway (Sinnett-Smith et al, 1993; Zachary et al, 1993; Seufferlein and Rozengurt, 1994). It is possible that tyrosine phosphorylation of p125FAK by bombesin, LPA and pp60v-src bypasses and perhaps mimics the phosphorylation caused by integrin activation. Further experimental work will be required to elucidate whether integrins and neuropeptides increase the autophosphorylation of Tyr-397 in p125FAK, as has been recently demonstrated in src-transformed cells (Schaller et al, 1994). Thus, molecular and cellular aspects of the role of p125FAK in signal transduction remain unclear. Specifically, the molecular steps by which different receptors (integrins, seven transmembrane domain receptors and tyrosine kinase receptors) can transduce signals leading to p125FAK tyrosine phosphorylation and the precise role of p125FAK in cell regulation are important areas for further research. Identification of the substrates of p125FAK, which given its localization are likely to reside in or be associated with focal adhesion, will be crucial for elucidating its role in cell regulation.

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