Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UK.
Cell Rep. 2017 Oct 31;21(5):1386-1398. doi: 10.1016/j.celrep.2017.10.042.
Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions.
蛋白质激酶被招募到 Hsp90 系统是由衔接共伴侣 Cdc37 介导的。我们发现 CDK4 和 CDK6 组装成蛋白复合物的过程受到 Cdc37-Hsp90 系统的差异调控。与其他 Hsp90 激酶客户一样，CDK4/6 与 Cdc37 的结合被 ATP 竞争抑制剂所阻断。Cdc37-Hsp90 将 CDK6 释放给 D 型和病毒型细胞周期蛋白以及 INK 家族 CDK 抑制剂，而 CDK4 则被释放给 INKs，但不太容易被细胞周期蛋白释放。p21CIP1 和 p27KIP1 CDK 抑制剂在从 Cdc37 上置换 CDK4 和 CDK6 方面的效力不如 INKs。然而，它们与 D 型细胞周期蛋白合作，生成含有 CDK4/6 的三元复合物，这些复合物对 Cdc37 置换细胞周期蛋白 D 具有抗性，这表明存在一种分子机制可以解释 CIP/KIP 家族成员的组装因子活性。总的来说，我们的数据揭示了 Hsp90 系统在不同细胞条件下控制 CDK4 和 CDK6-细胞周期蛋白复合物形成的多种机制。
