Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia
Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia
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DOI：
10.1038/sj.emboj.7601057
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发表时间：
2006-04-19
期刊：
影响因子：
11.4
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Liu, Wei;Rui, Hongliang;Lin, Sheng-Cai
tgf - β信号涉及广泛的信号分子和多个控制事件。支架蛋白创建信号分子的功能接近并控制信号转导的特异性。虽然参与tgf - β途径的许多成分已经被阐明，但对这些成分如何与支架蛋白协调知之甚少。在这里，我们发现Axin通过形成由Smad7和泛素E3连接酶Arkadia组成的多聚体复合物激活tgf - β信号传导。Axin依赖Arkadia促进tgf - β信号传导，因为它们的小干扰rna相互抵消了对tgf - β信号传导的刺激作用。Axin或Arkadia特异性敲低表明Axin和Arkadia相互合作促进Smad7泛素化。脉冲追踪实验进一步证明，Axin显著降低Smad7的半衰期。Axin也诱导Smad7的核输出。有趣的是，Axin与Arkadia和Smad7的关联独立于tgf - β信号，而不是与无活性Smad3的短暂关联。然而，Wnt-1的共表达通过下调Axin水平降低Smad7泛素化，强调了Axin作为tgf - β信号传导的内在调节因子的重要性。
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 down-regulating Axin levels, underscoring the importance of Axin as an intrinsic regulator in TGF-beta signaling.