Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway

Curr Biol. 2001 Nov 13;11(22):1759-65. doi: 10.1016/s0960-9822(01)00538-3.


C-Abl is a nonreceptor tyrosine kinase that is tightly regulated in the cell. Genetic data derived from studies in flies and mice strongly support a role for Abl kinases in the regulation of the cytoskeleton (reviewed in [1,2]). C-Abl can be activated by several stimuli, including oxidative stress [3], DNA damage [4], integrin engagement [5], growth factors, and Src family kinases [6]. Structural alterations elicit constitutive activation of the c-Abl tyrosine kinase, leading to oncogenic transformation. While the mechanisms that activate c-Abl are beginning to be elucidated, little is known regarding the mechanisms that downregulate activated c-Abl. Here, we show for the first time that activated c-Abl is downregulated by the ubiquitin-dependent degradation pathway. Activated forms of c-Abl are more unstable than wild-type and kinase-inactive forms. Moreover, inhibition of the 26S proteasome leads to increased c-Abl levels in vitro and in cells, and activated c-Abl proteins are ubiquitinated in vivo. Significantly, inhibition of the 26S proteasome in fibroblasts increases the levels of tyrosine-phosphorylated, endogenous c-Abl. Our data suggest a novel mechanism for irreversible downregulation of activated c-Abl, which is critical to prevent the deleterious consequences of c-Abl hyperactivation in mitogenic and cytoskeletal pathways.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Enzyme Activation
  • Enzyme Stability
  • Mice
  • Peptide Hydrolases / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex*
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Signal Transduction*
  • Tyrosine / metabolism
  • Ubiquitin / metabolism*


  • Ubiquitin
  • Tyrosine
  • Proto-Oncogene Proteins c-abl
  • Peptide Hydrolases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease