Inhibition of c-Abl tyrosine kinase activity by filamentous actin

J Biol Chem. 2001 Jul 20;276(29):27104-10. doi: 10.1074/jbc.M100559200. Epub 2001 Apr 17.

Abstract

The catalytic activity of c-Abl tyrosine kinase is reduced in fibroblasts that are detached from the extracellular matrix. We report here that a deletion of the extreme C terminus of c-Abl (DeltaF-actin c-Abl) can partially restore kinase activity to c-Abl from detached cells. Because the extreme C terminus of c-Abl contains a consensus F-actin binding motif, we investigated the effect of F-actin on c-Abl tyrosine kinase activity. We found that F-actin can inhibit the kinase activity of purified c-Abl protein. Mutations of the extreme C-terminal region of c-Abl disrupted both the binding of c-Abl to F-actin and the inhibition of c-Abl by F-actin. Mutations of the SH3, SH2, and DNA binding domains did not abolish the inhibition of c-Abl kinase by F-actin. Catalytic domain substitutions that affect the regulation of c-Abl by the retinoblastoma protein or the ataxia telangiectasia-mutated kinase also did not abolish the inhibition of c-Abl by F-actin. Interestingly, among these c-Abl mutants, only the DeltaF-actin c-Abl retained kinase activity in detached cells. Taken together, the data suggest that F-actin is an inhibitor of the c-Abl tyrosine kinase and that this inhibition contributes in part to the reduced Abl kinase activity in detached cells.

Publication types

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

MeSH terms

  • Actins / metabolism*
  • Animals
  • Cell Line
  • Mice
  • Protein Binding
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / metabolism

Substances

  • Actins
  • Proto-Oncogene Proteins c-abl