title: Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling.
abstract: Here we describe a mechanism that cancer cells use to survive when flux through the Src/FAK pathway is severely perturbed. Depletion of FAK, detachment of FAK-proficient cells or expression of non-phosphorylatable FAK proteins causes sequestration of active Src away from focal adhesions into intracellular puncta that co-stain with several autophagy regulators. Inhibition of autophagy results in restoration of active Src at peripheral adhesions, and this leads to cancer cell death. Autophagic targeting of active Src is associated with a Src-LC3B complex, and is mediated by c-Cbl. However, this is independent of c-Cbl E3 ligase activity, but is mediated by an LC3-interacting region. Thus, c-Cbl-mediated autophagic targeting of active Src can occur in cancer cells to maintain viability when flux through the integrin/Src/FAK pathway is disrupted. This exposes a previously unrecognized cancer cell vulnerability that may provide a new therapeutic opportunity.
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Sandilands
authors.forename: Bryan
authors.initials: B
authors.lastname: Serrels
authors.forename: David G
authors.initials: DG
authors.lastname: McEwan
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Macagno
authors.forename: Kenneth
authors.initials: K
authors.lastname: McLeod
authors.forename: Craig
authors.initials: C
authors.lastname: Stevens
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Simon
authors.initials: S
authors.lastname: Wilkinson
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Frame
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016023:Integrins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D050721:Proto-Oncogene Proteins c-cbl; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; C493849:Cbl protein, mouse