Targeted proteolysis of the focal adhesion kinase pp125 FAK during c-MYC-induced apoptosis is suppressed by integrin signalling.
The product of the c-myc proto-oncogene has a central role in induction of apoptosis, a physiological form of cell death characterised in vitro by morphological rounding, detachment and nuclear disintegration. Induction of apoptosis by serum withdrawal from c-Myc-transformed chicken embryo fibroblasts (CEF) results in early proteolysis of focal adhesion kinase (ppl25FAK), a tyrosine kinase implicated in the conversion of integrin signals into their biological responses. Proteolysis of pp125 FAK occurs in adherent cells prior to commitment to death, suggesting 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 pp125FAK are coordinately suppressed by treating with insulin or plating on the extracellular matrix components collagen and fibronectin. In addition, proteolysis of pp125FAK is suppressed by a beta1-specific integrin antibody, which promotes cell survival in the face of the oncoprotein-induced signal for apoptosis. These results provide compelling evidence that the c-Myc-induced cell death programme in CEF requires disruption of the integrin signalling pathways which normally function when cells are spread on ECM, and that maintaining cellular pp125FAK, which couples integrins to their downstream effectors, is closely linked to cell survival.
Crouch
D H
DH
The Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Glascow, UK.
Fincham
V J
VJ
Frame
M C
MC
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism; D016895:Culture Media, Serum-Free; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D000906:Antibodies; D015815:Cell Adhesion Molecules; D016895:Culture Media, Serum-Free; D019012:Integrin beta1; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases