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首页> 外文期刊>Current Biology: CB >Regulation of Cyclin-Substrate Docking by a G1 Arrest Signaling Pathway and the Cdk Inhibitor Far1
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Regulation of Cyclin-Substrate Docking by a G1 Arrest Signaling Pathway and the Cdk Inhibitor Far1

机译：G1逮捕信号通路和Cdk抑制剂Far1对细胞周期蛋白-底物对接的调控。

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摘要

Eukaryotic cell division is often regulated by extracellular signals. In budding yeast, signaling from mating pheromones arrests the cell cycle in G1 phase [1]. This arrest requires the protein Far1 [2], which is thought to antagonize the G1/S transition by acting as a Cdk inhibitor (CKI) [3, 4], although the mechanisms remain unresolved [5]. Recent studies found that G1/S cyclins (Cln1 and Cln2) recognize Cdk substrates via specific docking motifs, which promote substrate phosphorylation in vivo [6, 7]. Here, we show that these docking interactions are inhibited by pheromone signaling and that this inhibition requires Far1 Moreover, Far1 mutants that cannot inhibit docking are defective at cell-cycle arrest. Consistent with this arrest function, Far1 outcompetes substrates for association with G1/S cyclins in vivo, and it is present in large excess over G1/S cyclins during the precommitment period where pheromone can impose G1 arrest. Finally, a comparison of substrates that do and do not require docking suggests that Far1 acts as a multimode inhibitor that antagonizes both kinase activity and substrate recognition by Cln1/2-Cdk complexes. Our findings uncover a novel mechanism of Cdk regulation by external signals and shed new light on Far1 function to provide a revised view of cell-cycle arrest in this model system.
机译：真核细胞分裂通常受细胞外信号调节。在发芽酵母中，来自交配信息素的信号将细胞周期停滞在G1期[1]。这种逮捕需要蛋白质Far1 [2]，尽管其机理尚未解决[5]，但人们认为它可以通过充当Cdk抑制剂（CKI）来拮抗G1 / S过渡[3，4]。最近的研究发现，G1 / S细胞周期蛋白（Cln1和Cln2）通过特定的对接基序识别Cdk底物，从而促进体内的底物磷酸化[6，7]。在这里，我们表明这些对接相互作用被信息素信号传导所抑制，并且这种抑制作用需要Far1。而且，不能抑制对接的Far1突变体在细胞周期停滞中是有缺陷的。与这种阻滞功能一致，Far1在体内与G1 / S细胞周期蛋白缔合的底物竞争性强，并且在信息素可强加G1阻滞的预承诺期，它比G1 / S细胞周期蛋白的过量存在。最后，对需要停靠和不需要停靠的底物的比较表明，Far1作为多模抑制剂，可拮抗激酶活性和Cln1 / 2-Cdk复合物对底物的识别。我们的发现揭示了一种通过外部信号调节Cdk的新机制，并为Far1功能提供了新的思路，从而提供了该模型系统中细胞周期停滞的修正视图。

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