Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases
Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases
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DOI：
10.1074/jbc.m414027200
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发表时间：
2005-06-10
影响因子：
4.8
通讯作者：
Moustakas, A
中科院分区：
文献类型：
--
作者：
Morén, A;Imamura, T;Moustakas, A
Smad4通过转化生长因子-β(TGF-β)超家族细胞因子介导信号传导。Smad信号受抑制性(I)Smads和泛素介导的过程的负调控。已知的Smads蛋白酶体降解机制依赖于特定的E3连接酶与Smads的直接相互作用。或者，I-Smads通过招募WW和Hect结构域的E3连接酶、蓝精灵、WWP1或NEDD4-2来诱导转化生长因子-β受体的降解。我们描述了上述E3连接酶降解Smad4的一个等效机制，即在R-Smads(Smad2)或I-Smads(Smad6/7)的作用下，Smad4与蓝精灵之间形成三元复合体，作为接头。否则不能直接与Smad4结合的蓝精灵在Smad6或Smad7存在的情况下介导Smad4的多泛素化。Smad4与Smad7和SMurf1共定位于细胞质和外周细胞突起。Smad4相互作用缺陷的Smad2或Smad7突变体不能诱导Smad1介导的Smad4下调。在Smad2或Smad7相互作用中有缺陷的Smad4突变体不能有效地被SMurf1下调。我们认为，Smad4可以被同时作用于R-Smads和信号受体的多个泛素连接酶降解。这种下调转化生长因子-β信号的机制可能是对这一途径做出适当生理反应的关键。
Smad4 mediates signaling by the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Smad signaling is negatively regulated by inhibitory (I) Smads and ubiquitin-mediated processes. Known mechanisms of proteasomal degradation of Smads depend on the direct interaction of specific E3 ligases with Smads. Alternatively, I-Smads elicit degradation of the TGF-beta receptor by recruiting the WW and HECT domain E3 ligases, Smurfs, WWP1, or NEDD4-2. We describe an equivalent mechanism of degradation of Smad4 by the above E3 ligases, via formation of ternary complexes between Smad4 and Smurfs, mediated by R-Smads (Smad2) or I-Smads (Smad6/7), acting as adaptors. Smurfs, which otherwise cannot directly bind to Smad4, mediated polyubiquitination of Smad4 in the presence of Smad6 or Smad7. Smad4 co-localized with Smad7 and Smurf1 primarily in the cytoplasm and in peripheral cell protrusions. Smad2 or Smad7 mutants defective in Smad4 interaction failed to induce Smurf1-mediated down-regulation of Smad4. A Smad4 mutant defective in Smad2 or Smad7 interaction could not be effectively down-regulated by Smurf1. We propose that Smad4 is targeted for degradation by multiple ubiquitin ligases that can simultaneously act on R-Smads and signaling receptors. Such mechanisms of down-regulation of TGF-beta signaling may be critical for proper physiological response to this pathway.