Axin and GSK3-β control Smad3 protein stability and modulate TGF-β signaling Journal Article uri icon

Overview

abstract

  • The broad range of biological responses elicited by transforming growth factor-β (TGF-β) in various types of tissues and cells is mainly determined by the expression level and activity of the effector proteins Smad2 and Smad3. It is not fully understood how the baseline properties of Smad3 are regulated, although this molecule is in complex with many other proteins at the steady state. Here we show that nonactivated Smad3, but not Smad2, undergoes proteasome-dependent degradation due to the concerted action of the scaffolding protein Axin and its associated kinase, glycogen synthase kinase 3-β (GSK3-β). Smad3 physically interacts with Axin and GSK3-β only in the absence of TGF-β. Reduction in the expression or activity of Axin/GSK3-β leads to increased Smad3 stability and transcriptional activity without affecting TGF-β receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-β. Mechanistically, Axin facilitates GSK3-β-mediated phosphorylation of Smad3 at Thr66, which triggers Smad3 ubiquitination and degradation. Thr66 mutants of Smad3 show altered protein stability and hence transcriptional activity. These results indicate that the steady-state stability of Smad3 is an important determinant of cellular sensitivity to TGF-β, and suggest a new function of the Axin/GSK3-β complex in modulating critical TGF-β/Smad3-regulated processes during development and tumor progression.

publication date

  • January 1, 2008

Date in CU Experts

  • February 16, 2014 2:41 AM

Full Author List

  • Guo X; Ramirez A; Waddell DS; Li Z; Liu X; Wang X-F

author count

  • 6

Other Profiles

International Standard Serial Number (ISSN)

  • 0890-9369

Electronic International Standard Serial Number (EISSN)

  • 1549-5477

Additional Document Info

start page

  • 106

end page

  • 120

volume

  • 22

issue

  • 1