期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 27, 期 5, 页码 1809-1822出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01051-06
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资金
- NCI NIH HHS [R01 CA082391, R24 CA088336, R55 CA082391, CA82391] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007158, T32DK-007158-30] Funding Source: Medline
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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