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首页> 外文期刊>Cell discovery. >TORC1 coordinates the conversion of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1
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TORC1 coordinates the conversion of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1

机译：TORC1协调Sic1从靶标转化为细胞周期蛋白CDK-Cks1抑制剂

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摘要

Eukaryotic cell cycle progression through G1–S is driven by hormonal and growth-related signals that are transmitted by the target of rapamycin complex 1 (TORC1) pathway. In yeast, inactivation of TORC1 restricts G1–S transition due to the rapid clearance of G1 cyclins (Cln) and the stabilization of the B-type cyclin (Clb) cyclin-dependent kinase (CDK) inhibitor Sic1. The latter mechanism remains mysterious but requires the phosphorylation of Sic1-Thr173 by Mpk1 and inactivation of the Sic1-pThr173-targeting phosphatase (PP2ACdc55) through greatwall kinase-activated endosulfines. Here we show that the Sic1-pThr173 residue serves as a specific docking site for the CDK phospho-acceptor subunit Cks1 that sequesters, together with a C-terminal Clb5-binding motif in Sic1, Clb5-CDK-Cks1 complexes, thereby preventing them from flagging Sic1 for ubiquitin-dependent proteolysis. Interestingly, this functional switch of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1 also operates in proliferating cells and is coordinated by the greatwall kinase, which responds to both Cln-CDK-dependent cell-cycle and TORC1-mediated nutritional cues.
机译：雷帕霉素复合物1（TORC1）靶标传递的激素和生长相关信号驱动着通过G 1 -S的真核细胞周期进程。在酵母中，由于G 1 细胞周期蛋白（Cln）的快速清除和B型细胞周期蛋白（Clb）的稳定，TORC1的失活限制了G 1 –S的转变。细胞周期蛋白依赖性激酶（CDK）抑制剂Sic1。后者的机制仍然是未知的，但是需要Mpk1使Sic1-Thr 173 磷酸化，并使靶向Sic1-pThr 173 的磷酸酶（PP2A Cdc55 ）通过长壁激酶激活的内硫。在这里，我们显示Sic1-pThr 173 残基充当CDK磷酸受体亚基Cks1螯合的特定停靠位点，以及Sic1，Clb5-CDK中的C端Clb5结合基序-Cks1复合物，从而防止它们将Sic1标记为泛素依赖性蛋白水解。有趣的是，Sic1从靶标向细胞周期蛋白-CDK-Cks1抑制剂的这种功能转换也在增殖细胞中起作用，并受到长壁激酶的协调，该长壁激酶对Cln-CDK依赖性细胞周期和TORC1介导的营养线索均做出反应。

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