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

Publication ,  Journal Article
Echarri, A; Pendergast, AM
Published in: Curr Biol
November 13, 2001

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.

Duke Scholars

Published In

Curr Biol

DOI

ISSN

0960-9822

Publication Date

November 13, 2001

Volume

11

Issue

22

Start / End Page

1759 / 1765

Location

England

Related Subject Headings

  • Ubiquitin
  • Tyrosine
  • Signal Transduction
  • Proto-Oncogene Proteins c-abl
  • Proteasome Endopeptidase Complex
  • Phosphorylation
  • Peptide Hydrolases
  • Mice
  • Enzyme Stability
  • Enzyme Activation
 

Citation

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Echarri, A., & Pendergast, A. M. (2001). Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Curr Biol, 11(22), 1759–1765. https://doi.org/10.1016/s0960-9822(01)00538-3
Echarri, A., and A. M. Pendergast. “Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway.Curr Biol 11, no. 22 (November 13, 2001): 1759–65. https://doi.org/10.1016/s0960-9822(01)00538-3.
Echarri A, Pendergast AM. Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Curr Biol. 2001 Nov 13;11(22):1759–65.
Echarri, A., and A. M. Pendergast. “Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway.Curr Biol, vol. 11, no. 22, Nov. 2001, pp. 1759–65. Pubmed, doi:10.1016/s0960-9822(01)00538-3.
Echarri A, Pendergast AM. Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Curr Biol. 2001 Nov 13;11(22):1759–1765.
Journal cover image

Published In

Curr Biol

DOI

ISSN

0960-9822

Publication Date

November 13, 2001

Volume

11

Issue

22

Start / End Page

1759 / 1765

Location

England

Related Subject Headings

  • Ubiquitin
  • Tyrosine
  • Signal Transduction
  • Proto-Oncogene Proteins c-abl
  • Proteasome Endopeptidase Complex
  • Phosphorylation
  • Peptide Hydrolases
  • Mice
  • Enzyme Stability
  • Enzyme Activation