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Mol Cell Biol. 2007 Mar;27(5):1809-22. Epub 2006 Dec 18.

Regulation of proto-oncogenic dbl by chaperone-controlled, ubiquitin-mediated degradation.

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  • 1Case School of Medicine, WG-48, Case Western Reserve University, Cleveland, OH 44106, USA. danny.manor@case.edu

Abstract

The dbl proto-oncogene product is a prototype of a growing family of guanine nucleotide exchange factors (GEFs) that stimulate the activation of small GTP-binding proteins from the Rho family. Mutations that result in the loss of proto-Dbl's amino terminus produce a variant with constitutive GEF activity and high oncogenic potential. Here, we show that proto-Dbl is a short-lived protein that is kept at low levels in cells by efficient ubiquitination and degradation. The cellular fate of proto-Dbl is regulated by interactions with the chaperones Hsc70 and Hsp90 and the protein-ubiquitin ligase CHIP, and these interactions are mediated by the spectrin domain of proto-Dbl. We show that CHIP is the E3 ligase responsible for ubiquitination and proteasomal degradation of proto-Dbl, while Hsp90 functions to stabilize the protein. Onco-Dbl, lacking the spectrin homology domain, cannot bind these regulators and therefore accumulates in cells at high levels, leading to persistent stimulation of its downstream signaling pathways.

PMID:
17178836
[PubMed - indexed for MEDLINE]
PMCID:
PMC1820456
Free PMC Article
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