Cullin 5 destabilizes cas to inhibit src-dependent cell transformation

Anjali Teckchandani, George S. Laszlo, Sergi Simo Olivar, Khyati Shah, Carissa Pilling, Alexander A. Strait, Jonathan A. Cooper

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 (Crkassociated substrate). Phosphorylation stimulates Cas binding to the Cul5-CRL adaptor protein SOCS6 and consequent proteasomedependent 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.

Original languageEnglish (US)
Pages (from-to)509-520
Number of pages12
JournalJournal of Cell Science
Volume127
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

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Keywords

  • Cas
  • Cul5
  • Cullin 5
  • Migration
  • Src
  • Transformation
  • Ubiquitin

ASJC Scopus subject areas

  • Cell Biology

Cite this

Teckchandani, A., Laszlo, G. S., Simo Olivar, S., Shah, K., Pilling, C., Strait, A. A., & Cooper, J. A. (2014). Cullin 5 destabilizes cas to inhibit src-dependent cell transformation. Journal of Cell Science, 127(3), 509-520. https://doi.org/10.1242/jcs.127829