Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia

Wei Liu, Hongliang Rui, Jifeng Wang, Shuyong Lin, Ying He, Mingliang Chen, Qinxi Li, Zhiyun Ye, Suping Zhang, Chiu Chan Siu, Ye Guang Chen, Jiahuai Han, Sheng Cai Lin

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

TGF-β signaling involves a wide array of signaling molecules and multiple controlling events. Scaffold proteins create a functional proximity of signaling molecules and control the specificity of signal transduction. While many components involved in the TGF-β pathway have been elucidated, little is known about how those components are coordinated by scaffold proteins. Here, we show that Axin activates TGF-β signaling by forming a multimeric complex consisting of Smad7 and ubiquitin E3 ligase Arkadia. Axin depends on Arkadia to facilitate TGF-β signaling, as their small interfering RNAs reciprocally abolished the stimulatory effect on TGF-β signaling. Specific knockdown of Axin or Arkadia revealed that Axin and Arkadia cooperate with each other in promoting Smad7 ubiquitination. Pulse-chase experiments further illustrated that Axin significantly decreased the half-life of Smad7. Axin also induces nuclear export of Smad7. Interestingly, Axin associates with Arkadia and Smad7 independently of TGF-β signal, in contrast to its transient association with inactive Smad3. However, coexpression of Wnt-1 reduced Smad7 ubiquitination by downregulating Axin levels, underscoring the importance of Axin as an intrinsic regulator in TGF-β signaling.

Original languageEnglish (US)
Pages (from-to)1646-1658
Number of pages13
JournalEMBO Journal
Volume25
Issue number8
DOIs
StatePublished - Apr 19 2006
Externally publishedYes

Keywords

  • Arkadia
  • Axin
  • Smad7
  • TGF-β
  • Ubiquitination

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