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

Nat Cell Biol. 2011 Dec 4;14(1):51-60. doi: 10.1038/ncb2386.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Adhesion / physiology
  • Cell Survival / physiology
  • Focal Adhesion Kinase 1 / biosynthesis
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Immunoprecipitation
  • Integrins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured
  • src-Family Kinases / metabolism*

Substances

  • Integrins
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins c-cbl
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • src-Family Kinases
  • Cbl protein, mouse