Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway.
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Echarri, A; Pendergast, AM
Published Date
- November 13, 2001
Published In
Volume / Issue
- 11 / 22
Start / End Page
- 1759 - 1765
PubMed ID
- 11719217
Pubmed Central ID
- 11719217
International Standard Serial Number (ISSN)
- 0960-9822
Digital Object Identifier (DOI)
- 10.1016/s0960-9822(01)00538-3
Language
- eng
Conference Location
- England