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Jab1 antagonizes TGF‐β signaling by inducing Smad4 degradation
Author(s) -
Wan Mei,
Cao Xuesong,
Wu Yalei,
Bai Shuting,
Wu Liyu,
Shi Xingming,
Wang Ning,
Cao Xu
Publication year - 2002
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1093/embo-reports/kvf024
Subject(s) - mg132 , microbiology and biotechnology , smad , lactacystin , proteasome , biology , transcription factor , signal transduction , transforming growth factor beta , ubiquitin , ectopic expression , transforming growth factor , smad2 protein , effector , phosphorylation , ubiquitin ligase , transcription (linguistics) , proteasome inhibitor , biochemistry , gene , linguistics , philosophy
Tumor suppressor Smad4 is the common signaling effector in the transforming growth factor β (TGF‐β) superfamily. Phosphorylated regulatory Smads (R‐Smads) interact with Smad4, and the complex translocates into the nucleus to regulate gene transcription. Proper TGF‐β signaling requires precise control of Smad functions. Smurfs have been shown to mediate the degradation of R‐Smads but not the common‐partner Smad4. We report a novel mechanism of Smad4 degradation. Jab1 interacts directly with Smad4 and induces its ubiquitylation for degradation. Jab1 was initially identified as a co‐activator of c‐Jun, and it also induces degradation of cell cycle inhibitor p27 and tumor suppressor p53. Ectopic expression of Jab1 decreased endogenous Smad4 steady‐state levels. The 26S proteasome inhibitors lactacystin and MG132 reduced the degradation rate of Smad4 protein. Examination of the effects of JAB1‐induced Smad4 degradation indicates that Jab1 inhibited TGF‐β‐induced gene transcription. Our data suggest that Jab1 antagonizes TGF‐β function by inducing degradation of Smad4 through a distinct degradation pathway.