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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{triangledown}

Elena Kamynina,{dagger} Krista Kauppinen,{dagger} 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.

* Corresponding author. Present address: Case School of Medicine, WG-48, Case Western Reserve University, Cleveland, OH 44106. Phone: (216) 368-6230. Fax: (216) 368-6644. E-mail: danny.manor{at}case.edu.

{triangledown} Published ahead of print on 18 December 2006.

{dagger} These authors contributed equally to this work.

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.



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