Cullin 5 destabilizes Cas to inhibit Src-dependent cell transformation

J Cell Sci. 2014 Feb 1;127(Pt 3):509-20. doi: 10.1242/jcs.127829. Epub 2013 Nov 27.


Phosphorylation-dependent protein ubiquitylation and degradation provides an irreversible mechanism to terminate protein kinase signaling. Here, we report that mammary epithelial cells require cullin-5-RING-E3-ubiquitin-ligase complexes (Cul5-CRLs) to prevent transformation by a Src-Cas signaling pathway. Removal of Cul5 stimulates growth-factor-independent growth and migration, membrane dynamics and colony dysmorphogenesis, which are all dependent on the endogenous tyrosine kinase Src. Src is activated in Cul5-deficient cells, but Src activation alone is not sufficient to cause transformation. We found that Cul5 and Src together stimulate degradation of the Src substrate p130Cas (Crk-associated substrate). Phosphorylation stimulates Cas binding to the Cul5-CRL adaptor protein SOCS6 and consequent proteasome-dependent degradation. Cas is necessary for the transformation of Cul5-deficient cells. Either knockdown of SOCS6 or use of a degradation-resistant Cas mutant stimulates membrane ruffling, but not other aspects of transformation. Our results show that endogenous Cul5 suppresses epithelial cell transformation by several pathways, including inhibition of Src-Cas-induced ruffling through SOCS6.

Keywords: Cas; Cul5; Cullin 5; Migration; Src; Transformation; Ubiquitin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Movement / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Crk-Associated Substrate Protein / metabolism*
  • Cullin Proteins / genetics*
  • Cullin Proteins / metabolism
  • Epithelial Cells / metabolism
  • Gene Knockdown Techniques
  • Mice
  • Signal Transduction / genetics
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Crk-Associated Substrate Protein
  • Cullin Proteins
  • Socs6 protein, mouse
  • Suppressor of Cytokine Signaling Proteins
  • cullin5 protein, mouse
  • src-Family Kinases