Jab1 Antagonizes TGF-beta Signaling by Inducing Smad4 Degradation

EMBO Rep. 2002 Feb;3(2):171-6. doi: 10.1093/embo-reports/kvf024. Epub 2002 Jan 29.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Peptide Hydrolases
  • Precipitin Tests
  • Protein Interaction Mapping
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription Factors / physiology*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / physiology*

Substances

  • DNA-Binding Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Peptide Hydrolases