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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.

Pubmed ID: 11818334

Authors

  • Wan M
  • Cao X
  • Wu Y
  • Bai S
  • Wu L
  • Shi X
  • Wang N
  • Cao X

Journal

EMBO reports

Publication Data

February 6, 2002

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK53757
  • Agency: NIDDK NIH HHS, Id: DK57501

Mesh Terms

  • Animals
  • COS Cells
  • DNA-Binding Proteins
  • Peptide Hydrolases
  • Precipitin Tests
  • Protein Interaction Mapping
  • Signal Transduction
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta