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Axin and GSK3-β control Smad3 protein stability and modulate TGF-β signaling

机译:Axin和GSK3-β控制Smad3蛋白稳定性并调节TGF-β信号传导

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摘要

The broad range of biological responses elicited by transforming growth factor-β (TGF-β) in various types of tissues and cells is mainly determined by the expression level and activity of the effector proteins Smad2 and Smad3. It is not fully understood how the baseline properties of Smad3 are regulated, although this molecule is in complex with many other proteins at the steady state. Here we show that nonactivated Smad3, but not Smad2, undergoes proteasome-dependent degradation due to the concerted action of the scaffolding protein Axin and its associated kinase, glycogen synthase kinase 3-β (GSK3-β). Smad3 physically interacts with Axin and GSK3-β only in the absence of TGF-β. Reduction in the expression or activity of Axin/GSK3-β leads to increased Smad3 stability and transcriptional activity without affecting TGF-β receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-β. Mechanistically, Axin facilitates GSK3-β-mediated phosphorylation of Smad3 at Thr66, which triggers Smad3 ubiquitination and degradation. Thr66 mutants of Smad3 show altered protein stability and hence transcriptional activity. These results indicate that the steady-state stability of Smad3 is an important determinant of cellular sensitivity to TGF-β, and suggest a new function of the Axin/GSK3-β complex in modulating critical TGF-β/Smad3-regulated processes during development and tumor progression.
机译:转化生长因子-β(TGF-β)在各种类型的组织和细胞中引起的广泛的生物学反应主要取决于效应蛋白Smad2和Smad3的表达水平和活性。尽管该分子在稳态下与许多其他蛋白质复合,但尚不完全了解如何调节Smad3的基线特性。在这里,我们显示未激活的Smad3(而非Smad2)由于脚手架蛋白Axin及其相关激酶,糖原合酶激酶3-β(GSK3-β)的协同作用而经历了蛋白酶体依赖性降解。 Smad3仅在不存在TGF-β的情况下与Axin和GSK3-β发生物理相互作用。 Axin /GSK3-β表达或活性的降低导致Smad3稳定性和转录活性增加,而不会影响TGF-β受体或Smad2,而这些蛋白的过度表达促进Smad3的基础降解并使细胞对TGF-β脱敏。从机理上讲,Axin有助于在Thr66处GSK3-β介导的Smad3磷酸化,从而触发Smad3泛素化和降解。 Smad3的Thr66突变体显示出改变的蛋白质稳定性,因此具有转录活性。这些结果表明,Smad3的稳态稳定性是细胞对TGF-β敏感性的重要决定因素,并表明Axin /GSK3-β复合物在发育过程中调节TGF-β/ Smad3关键调控过程的新功能。肿瘤进展。

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