Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-β signaling
Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-β signaling
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DOI：
10.1074/jbc.m701294200
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发表时间：
2007-07-13
影响因子：
4.8
通讯作者：
Miyazawa, Keiji
中科院分区：
文献类型：
--
作者：
Nagano, Yoshiko;Mavrakis, Konstantinos J.;Miyazawa, Keiji
转化生长因子-β（TGF-β）信号传导受多种调节剂控制，所述调节剂靶向信号传导受体或活化的Smad复合物。在负调节因子中，Smad 7主要通过靶向信号受体拮抗TGF-β信号传导，而SnoN和c-Ski通过Smad复合物的失活在转录水平上抑制信号传导。我们之前发现Arkadia是TGF-β信号传导的正调节因子，通过其C-末端RING结构域诱导Smad 7的泛素依赖性降解。我们在这里报告说，Arkadia诱导SnoN和c-Ski的降解，除了Smad 7。Arkadia与SnoN和c-Ski以其游离形式以及与Smad蛋白结合的形式相互作用，并组成性下调其表达水平。因此，Arkadia似乎通过同时下调两种不同类型的负调节因子Smad 7和SnoN/c-Ski来有效地增强TGF-β信号传导，并且可能在确定靶细胞中TGF-β家族信号传导的强度方面发挥重要作用。
Transforming growth factor-beta (TGF-beta) signaling is controlled by a variety of regulators that target either signaling receptors or activated Smad complexes. Among the negative regulators, Smad7 antagonizes TGF-beta signaling mainly through targeting the signaling receptors, whereas SnoN and c-Ski repress signaling at the transcriptional level through inactivation of Smad complexes. We previously found that Arkadia is a positive regulator of TGF-beta signaling that induces ubiquitin-dependent degradation of Smad7 through its C-terminal RING domain. We report here that Arkadia induces degradation of SnoN and c-Ski in addition to Smad7. Arkadia interacts with SnoN and c-Ski in their free forms as well as in the forms bound to Smad proteins, and constitutively down-regulates levels of their expression. Arkadia thus appears to effectively enhance TGF-beta signaling through simultaneous down-regulation of two distinct types of negative regulators, Smad7 and SnoN/c-Ski, and may play an important role in determining the intensity of TGF-beta family signaling in target cells.