Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells.
We have recently described that autophagic targeting of Src maintains cancer cell viability when FAK signalling is defective. Here, we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered/reduced FAK signalling, preventing its binding to FAK at integrin adhesions. Inhibition of autophagy restores Ret localization to focal adhesions. Importantly, Src kinase activity is required to target Ret to autophagosomes and enhance Ret degradation. Src is thus a general mediator of selective autophagic targeting of adhesion-linked kinases, and Ret a second FAK-binding tyrosine kinase degraded through autophagy in cancer cells under adhesion stress. Src--by controlling not only its own degradation but also that of other FAK-binding partners--allows cancer cell survival, suggesting a new therapeutic strategy.
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK. e.sandilands@ed.ac.uk
Emma
E
Sandilands
Bryan
B
Serrels
Simon
S
Wilkinson
Margaret C
MC
Frame
D000818:Animals; D001343:Autophagy; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D010588:Phagosomes / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D050721:Proto-Oncogene Proteins c-cbl; D051096:Proto-Oncogene Proteins c-ret; D051417:Focal Adhesion Kinase 1; D019061:src-Family Kinases