Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia.
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.
Liu
Wei
W
Department of Biochemistry, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
Rui
Hongliang
H
Wang
Jifeng
J
Lin
Shuyong
S
He
Ying
Y
Chen
Mingliang
M
Li
Qinxi
Q
Ye
Zhiyun
Z
Zhang
Suping
S
Chan
Siu Chiu
SC
Chen
Ye-Guang
YG
Han
Jiahuai
J
Lin
Sheng-Cai
SC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D025801:Ubiquitin / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D051155:Wnt1 Protein / Q000378:metabolism
D060466:Axin Protein; D012097:Repressor Proteins; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D051155:Wnt1 Protein; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases