TARGETED PROTEOLYSIS OF THE FOCAL ADHESION KINASE PP125(FAK) DURING C-MYC-INDUCED APOPTOSIS IS SUPPRESSED BY INTEGRIN SIGNALING

The product of the c-myc proto-oncogene has a central role in inductio n of apoptosis, a physiological form of cell death characterised ill v itro by morphological rounding, detachment and nuclear disintegration, Induction of apoptosis by serum withdrawal from c-Myc-transformed chi cken embryo fibroblasts (CEF) results in early proteolysis of focal ad hesion kinase (pp125(FAK)), a tyrosine kinase implicated in the conver sion of integrin signals into their biological responses, Proteolysis of pp125(FAK) occurs in adherent cells prior to commitment to death, s uggesting that it contributes to c-Myc-induced apoptosis, rather than being a consequence of it, Furthermore, c-Myc-induced detachment, cell death and cleavage of pp125(FAK) are coordinately suppressed by treat ing with insulin or plating on the extracellular matrix components col lagen and fibronectin, In addition, proteolysis of pp125(FAK) is suppr essed by a beta 1-specific integrin antibody, which promotes cell surv ival in the face of the oncoprotein-induced signal for apoptosis, Thes e results provide compelling evidence that the c-Myc-induced cell deat h programme in CEF requires disruption of the integrin signalling path ways which normally function when cells are spread on ECM, and that ma intaining cellular pp125(FAK), which couples integrins to their downst ream effecters, is closely linked to cell survival.