Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.
Tumor suppressor Smad4 is the common signaling effector in the transforming growth factor beta (TGF-beta) superfamily. Phosphorylated regulatory Smads (R-Smads) interact with Smad4, and the complex translocates into the nucleus to regulate gene transcription. Proper TGF-beta 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-beta-induced gene transcription. Our data suggest that Jab1 antagonizes TGF-beta function by inducing degradation of Smad4 through a distinct degradation pathway.
Wan
Mei
M
Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL 35294-0019, USA.
Cao
Xuesong
X
Wu
Yalei
Y
Bai
Shuting
S
Wu
Liyu
L
Shi
Xingming
X
Wang
Ning
N
Cao
Xu
X
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases; D011233:Precipitin Tests; D025941:Protein Interaction Mapping; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D004268:DNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D010447:Peptide Hydrolases