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首页> 外文期刊>Molecular and Cellular Biology >Ubiquitination and Proteolysis of Cancer-Derived Smad4 Mutants by SCFSkp2
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Ubiquitination and Proteolysis of Cancer-Derived Smad4 Mutants by SCFSkp2

机译：SCFSkp2对癌症衍生的Smad4突变体的泛素化和蛋白水解作用

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Smad4/DPC4, a common signal transducer in transforming growth factor beta (TGF-β) signaling, is frequently inactivated in human cancer. Although the ubiquitin-proteasome pathway has been established as one mechanism of inactivating Smad4 in cancer, the specific ubiquitin E3 ligase for ubiquitination-mediated proteolysis of Smad4 cancer mutants remains unclear. In this report, we identified the SCFSkp2 complex as candidate Smad4-interacting proteins in an antibody array-based screen and further elucidated the functions of SCFSkp2 in mediating the metabolic instability of cancer-derived Smad4 mutants. We found that Skp2, the F-box component of SCFSkp2, physically interacted with Smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to Skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the SCFSkp2 complex in switching cancer mutants of Smad4 to undergo polyubiquitination-dependent degradation.
机译：Smad4 / DPC4是转化生长因子β（TGF-β）信号传导的常见信号转导子，在人类癌症中经常失活。尽管已经建立了泛素-蛋白酶体途径作为灭活癌症中Smad4的一种机制，但尚不清楚用于泛素介导的Smad4癌症突变体蛋白水解的特异性泛素E3连接酶。在本报告中，我们在基于抗体阵列的筛选中将SCF Skp2 复合物鉴定为候选Smad4相互作用蛋白，并进一步阐明了SCF Skp2 在介导代谢不稳定性中的功能。癌症衍生的Smad4突变体。我们发现Skp2是SCF Skp2 的F-box成分，在生理水平上与Smad4发生物理相互作用。几种源自癌症的不稳定突变体表现出与Skp2的结合显着增加，这导致它们的泛素化增加和蛋白水解加速。这些结果表明SCF Skp2 复合物在转换Smad4的癌症突变体进行多泛素化依赖性降解中具有重要作用。

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