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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Cell Line, Cell Nucleus, Humans, Mice, Mutation, Phosphorylation, Protein Binding, Repressor Proteins, Signal Transduction, Smad3 Protein, Smad7 Protein, Transforming Growth Factor beta, Ubiquitin, Ubiquitin-Protein Ligases, Wnt1 Protein
EMBO J.
Date: Apr. 19, 2006
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