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Molecular and Cellular Biology, March 2007, p. 1809-1822, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01051-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of Proto-Oncogenic Dbl by Chaperone-Controlled, Ubiquitin-Mediated Degradation

Elena Kamynina, Krista Kauppinen, Faping Duan, Nora Muakkassa, and Danny Manor^*

Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853

Received 11 June 2006/ Returned for modification 27 June 2006/ Accepted 7 December 2006

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.

Published ahead of print on 18 December 2006.

These authors contributed equally to this work.

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