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Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling

Sandilands, Emma; Serrels, Bryan; McEwan, David G.; Morton, Jennifer P.; Macagno, Juan Pablo; McLeod, Kenneth; Stevens, Craig; Brunton, Valerie G.; Langdon, Wallace Y.; Vidal, Marcos; Sansom, Owen J.; Dikic, Ivan; Wilkinson, Simon; Frame, Margaret C.


Emma Sandilands

Bryan Serrels

David G. McEwan

Jennifer P. Morton

Juan Pablo Macagno

Kenneth McLeod

Valerie G. Brunton

Wallace Y. Langdon

Marcos Vidal

Owen J. Sansom

Ivan Dikic

Simon Wilkinson

Margaret C. Frame


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.

Journal Article Type Article
Publication Date 2012
Deposit Date Apr 3, 2014
Print ISSN 1465-7392
Electronic ISSN 1476-4679
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 14
Issue 1
Pages 51-60
Keywords Cancer; Src/FAK pathway; autophagic targeting;
Public URL
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