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Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling.

Publication ,  Journal Article
Guo, X; Ramirez, A; Waddell, DS; Li, Z; Liu, X; Wang, X-F
Published in: Genes Dev
January 1, 2008

The broad range of biological responses elicited by transforming growth factor-beta (TGF-beta) 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-beta (GSK3-beta). Smad3 physically interacts with Axin and GSK3-beta only in the absence of TGF-beta. Reduction in the expression or activity of Axin/GSK3-beta leads to increased Smad3 stability and transcriptional activity without affecting TGF-beta receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-beta. Mechanistically, Axin facilitates GSK3-beta-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-beta, and suggest a new function of the Axin/GSK3-beta complex in modulating critical TGF-beta/Smad3-regulated processes during development and tumor progression.

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Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

January 1, 2008

Volume

22

Issue

1

Start / End Page

106 / 120

Location

United States

Related Subject Headings

  • Wnt Proteins
  • Ubiquitin-Protein Ligases
  • Transforming Growth Factor beta
  • Threonine
  • Smad3 Protein
  • Signal Transduction
  • Repressor Proteins
  • Proteasome Endopeptidase Complex
  • Polyubiquitin
  • Phosphorylation
 

Citation

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Guo, X., Ramirez, A., Waddell, D. S., Li, Z., Liu, X., & Wang, X.-F. (2008). Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes Dev, 22(1), 106–120. https://doi.org/10.1101/gad.1590908
Guo, Xing, Alejandro Ramirez, David S. Waddell, Zhizhong Li, Xuedong Liu, and Xiao-Fan Wang. “Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling.Genes Dev 22, no. 1 (January 1, 2008): 106–20. https://doi.org/10.1101/gad.1590908.
Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang X-F. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes Dev. 2008 Jan 1;22(1):106–20.
Guo, Xing, et al. “Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling.Genes Dev, vol. 22, no. 1, Jan. 2008, pp. 106–20. Pubmed, doi:10.1101/gad.1590908.
Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang X-F. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes Dev. 2008 Jan 1;22(1):106–120.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

January 1, 2008

Volume

22

Issue

1

Start / End Page

106 / 120

Location

United States

Related Subject Headings

  • Wnt Proteins
  • Ubiquitin-Protein Ligases
  • Transforming Growth Factor beta
  • Threonine
  • Smad3 Protein
  • Signal Transduction
  • Repressor Proteins
  • Proteasome Endopeptidase Complex
  • Polyubiquitin
  • Phosphorylation