Regulation of Proto-Oncogenic Dbl by Chaperone-Controlled, Ubiquitin-Mediated Degradation
In: Molecular and Cellular Biology, Jg. 27 (2007-03-01), S. 1809-1822
Online
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Zugriff:
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.
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Regulation of Proto-Oncogenic Dbl by Chaperone-Controlled, Ubiquitin-Mediated Degradation
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Autor/in / Beteiligte Person: | Duan, Faping ; Manor, Danny ; Nora W Muakkassa ; Kauppinen, Krista P. ; Kamynina, Elena |
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Zeitschrift: | Molecular and Cellular Biology, Jg. 27 (2007-03-01), S. 1809-1822 |
Veröffentlichung: | Informa UK Limited, 2007 |
Medientyp: | unknown |
ISSN: | 1098-5549 (print) |
DOI: | 10.1128/mcb.01051-06 |
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