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Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation
Mei Wan1, Xuesong Cao, Yalei Wu
1Department of Pathology, University of Alabama at Birmingham School of Medicine, 1670 University Boulevard, VH G002, Birmingham, AL 35294-0019, USA.
Abstract:
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.
Insights
Jab1 targets the tumor suppressor Smad4 for degradation, antagonizing transforming growth factor beta (TGF-beta) signaling. This novel pathway involves Jab1-induced ubiquitylation and proteasomal breakdown of Smad4.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Smad4 is a key mediator in transforming growth factor beta (TGF-beta) signaling, essential for gene transcription.
- While Smurfs degrade regulatory Smads (R-Smads), Smad4 degradation mechanisms were previously unknown.
Purpose of the Study:
- To elucidate a novel mechanism for Smad4 degradation.
- To investigate the role of Jab1 in Smad4 regulation and TGF-beta signaling.
Main Methods:
- Investigated the interaction between Jab1 and Smad4 using biochemical assays.
- Assessed Smad4 ubiquitylation and degradation via proteasome inhibitors (lactacystin, MG132).
- Quantified the impact of Jab1 on TGF-beta-induced gene transcription.
Main Results:
- Jab1 directly interacts with Smad4, inducing its ubiquitylation and subsequent degradation by the 26S proteasome.
- Ectopic Jab1 expression reduced endogenous Smad4 levels.
- Jab1-mediated Smad4 degradation inhibited TGF-beta-induced gene transcription.
Conclusions:
- Jab1 antagonizes TGF-beta signaling by promoting Smad4 degradation through a novel pathway.
- This finding reveals a new mechanism controlling TGF-beta pathway activity and Smad4 stability.