Signaling Transducation of Brk and Its Regulation by Hsp90 in Concert with Ubiquitination
Date Issued
2005
Date
2005
Author(s)
Huang, Yuan-Ping
DOI
en-US
Abstract
Breast tumor kinase (Brk) is a Src-like family non-receptor tyrosine kinase over-expressed in most breast cancer cells. Previous studies have established the correlation of Brk expression and the progression of malignancy. However, the exact biological function of Brk and the molecular mechanism through which Brk contributes to tumor metastasis remain to be elucidated. In this thesis, we have identified Paxillin as a novel cytosolic substrate of Brk. Expression of Brk significantly enhanced tyrosine phosphorylation of Paxillin, and these two proteins interacted with each other in vivo. We also showed that both N-terminal LD region and C-terminal LIM domain of Paxillin could mediate interaction with Brk. Besides, we found Hsp90 interacts with Brk in vivo. Subsequent experiments demonstrated that active Brk is under the protection of Hsp90 that its inactivation by treatment of geldanamycin (GA) results in ubiquitination of Brk mediated by the ubiquitin ligase C-terminus of Hsc70 interacting protein (CHIP). Moreover, we found that EGF treatment stimulated protein turnover of Brk through ubiquitination catalyzing by the ubiquitin ligase Cbl that is activated in response to EGF signal. These data suggested signaling of Brk is escorted by Hsp90 and negatively regulated by Cbl/CHIP-mediated ubiquitination.
Subjects
乳癌激酶
泛素化
訊息傳遞
Brk
Hsp90
Ubiqitination
SDGs
Type
other
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