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首页> 外文期刊>Cell cycle >Protein phosphatase 4 is phosphorylated and inactivated by Cdk in response to spindle toxins and interacts with γ-tubulin
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Protein phosphatase 4 is phosphorylated and inactivated by Cdk in response to spindle toxins and interacts with γ-tubulin

机译：蛋白磷酸酶4被Cdk磷酸化并失活，以响应纺锤体毒素并与γ-微管蛋白相互作用

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摘要

Many pharmaceuticals used to treat cancer target the cell cycle or mitotic spindle dynamics, such as the anti-tumor drug, paclitaxel, which stabilizes microtubules. Here we show that, in cells arrested in mitosis with the spindle toxins, nocodazole, or paclitaxel, the endogenous protein phosphatase 4 (Ppp4) complex Ppp4c-R2-R3A is phosphorylated on its regulatory (R) subunits, and its activity is inhibited. The phosphorylations are blocked by roscovitine, indicating that they may be mediated by Cdk1-cyclin B. Endogenous Ppp4c is enriched at the centrosomes in the absence and presence of paclitaxel, nocodazole, or roscovitine, and the activity of endogenous Ppp4c-R2-R3A is inhibited from G1/S to the G2/M phase of the cell cycle. Endogenous γ-tubulin and its associated protein, γ-tubulin complex protein 2, both of which are essential for nucleation of microtubules at centrosomes, interact with the Ppp4 complex. Recombinant γ-tubulin can be phosphorylated by Cdk1-cyclin B or Brsk1 and dephosphorylated by Ppp4c-R2-R3A in vitro. The data indicate that Ppp4c-R2-R3A regulates microtubule organization at centrosomes during cell division in response to stress signals such as spindle toxins, paclitaxel, and nocodazole, and that inhibition of the Ppp4 complex may be advantageous for treatment of some cancers.
机译：许多用于治疗癌症的药物靶向细胞周期或有丝分裂纺锤体动力学，例如稳定微管的抗肿瘤药紫杉醇。在这里我们显示，在被纺锤体毒素，诺考达唑或紫杉醇抑制的有丝分裂中的细胞中，内源蛋白磷酸酶4（Ppp4）复合物Ppp4c-R2-R3A在其调节（R）亚基上被磷酸化，并且其活性受到抑制。磷酸化被roscovitine阻断，表明它们可能由Cdk1-cyclin B介导。在不存在和存在紫杉醇，诺考达唑或roscovitine的情况下，内源性Ppp4c在中心体富集，并且内源性Ppp4c-R2-R3A的活性为从细胞周期的G1 / S到G2 / M期被抑制。内源性γ-微管蛋白及其相关蛋白γ-微管蛋白复合蛋白2与Ppp4复合物相互作用，这两者对于在中心体处的微管成核必不可少。重组γ-微管蛋白可以在体外被Cdk1-cyclin B或Brsk1磷酸化，并被Ppp4c-R2-R3A磷酸化。数据表明，Ppp4c-R2-R3A响应应激信号（例如纺锤体毒素，紫杉醇和诺考达唑），在细胞分裂过程中调节着丝粒处的微管组织，并且抑制Ppp4复合物可能对某些癌症的治疗有利。

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