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  • The EMBO Journal (2006) 25, 1646 - 1658
  • doi:10.1038/sj.emboj.7601057

Published online: 6 April 2006

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

Wei Liu1, Hongliang Rui1,a, Jifeng Wang2, Shuyong Lin1, Ying He2, Mingliang Chen2, Qinxi Li2, Zhiyun Ye2, Suping Zhang3, Siu Chiu Chan1, Ye-Guang Chen3, Jiahuai Han2,4 and Sheng-Cai Lin1,2

  1. Department of Biochemistry, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China
  2. Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian, China
  3. State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China
  4. Department of Immunology, the Scripps Research Institute, La Jolla, CA, USA

Correspondence to:

Sheng-Cai Lin, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Tel.: +852 2358 7294; Fax: +852 2358 1552; E-mail: linsc@ust.hk or linsc@xmu.edu.cn

aPresent address: Department of Nephrology, the China-Japan Friendship Hospital, Beijing, China

Received 21 September 2005; Accepted 1 March 2006

TGF-beta 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-beta pathway have been elucidated, little is known about how those components are coordinated by scaffold proteins. Here, we show that Axin activates TGF-beta signaling by forming a multimeric complex consisting of Smad7 and ubiquitin E3 ligase Arkadia. Axin depends on Arkadia to facilitate TGF-beta signaling, as their small interfering RNAs reciprocally abolished the stimulatory effect on TGF-beta 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-beta 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-beta signaling.

  • Keywords:

    • Arkadia,
    • Axin,
    • Smad7,
    • TGF-beta,
    • ubiquitination