A chemical genetic screen for direct v-Src substrates reveals ordered assembly of a retrograde signaling pathway

Chem Biol. 2002 Jan;9(1):35-47. doi: 10.1016/s1074-5521(02)00086-8.

Abstract

Using an ATP analog that is a specific substrate for an analog-specific allele of v-Src, we identified several novel cytoskeletal substrates that control actin assembly processes. A screen for less abundant v-Src substrates revealed the scaffolding protein Dok-1 as a direct substrate of v-Src. Further studies suggest that v-Src phosphorylation sites on Dok-1 are critical for its binding to RasGAP and Csk, negative regulators of Src signaling. This results in the downregulation of growth-promoting signals of the Src family kinases and the Ras pathway. Identification of the direct substrates of v-Src leads to a model for the precise order of assembly of a retrograde signaling pathway in v-Src-transformed cells and has provided new insight into the balance between those signals that promote cell transformation mediated by v-Src catalyzed tyrosine phosphorylation and those that inhibit it.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • DNA-Binding Proteins*
  • Mice
  • Mutation
  • Oncogene Protein pp60(v-src) / genetics*
  • Oncogene Protein pp60(v-src) / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • RNA-Binding Proteins*
  • Signal Transduction*
  • Substrate Specificity

Substances

  • DNA-Binding Proteins
  • Dok1 protein, mouse
  • GAP-associated protein p62
  • Phosphoproteins
  • RNA-Binding Proteins
  • Oncogene Protein pp60(v-src)