Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation.
Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation.
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DOI：
10.1038/ncomms8437
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发表时间：
2015-06-16
影响因子：
16.6
通讯作者：
Malliri, Angeliki
中科院分区：
文献类型：
--
作者：
Whalley, Helen J.;Porter, Andrew P.;Diamantopoulou, Zoi;White, Gavin R. M.;Castaneda-Saucedo, Eduardo;Malliri, Angeliki
中心体分离对于两极纺锤体的形成和哺乳动物细胞有丝分裂过程中染色体的准确分离是至关重要的。Kinesin-5(EG5)是中心体分离所必需的微管马达，Tiam1及其底物Rac在早期有丝分裂中拮抗依赖于EG5的中心体分离，促进有效的染色体聚集。在这里，我们确定Tiam1的S1466是一个新的CDK1位点，它的磷酸化是Tiam1有丝分裂功能所必需的。我们发现，Tiam1的这种磷酸化是在中心体的前期激活I组p21激活的激酶(PAK)所必需的。此外，我们还证明了Pak1和Pak2都以一种依赖于激酶的方式抵消了中心体的分离，并证明了它们作用于Tiam1的下游。我们还表明，Ak1/2的缺失使细胞能够通过EG5抑制来逃避单极抑制，强调了这一信号通路对于开发EG5抑制剂作为癌症治疗药物的潜在重要性。由动蛋白EG5促进的中心体分离被鸟嘌呤核苷酸交换因子Tiam1通过未知的机制拮抗。这里，Whalley等人。研究表明，Tiam1在前期被细胞周期蛋白依赖的激酶1磷酸化，导致p21激活的蛋白激酶(PAK)下游激活。
Centrosome separation is critical for bipolar spindle formation and the accurate segregation of chromosomes during mammalian cell mitosis. Kinesin-5 (Eg5) is a microtubule motor essential for centrosome separation, and Tiam1 and its substrate Rac antagonize Eg5-dependent centrosome separation in early mitosis promoting efficient chromosome congression. Here we identify S1466 of Tiam1 as a novel Cdk1 site whose phosphorylation is required for the mitotic function of Tiam1. We find that this phosphorylation of Tiam1 is required for the activation of group I p21-activated kinases (Paks) on centrosomes in prophase. Further, we show that both Pak1 and Pak2 counteract centrosome separation in a kinase-dependent manner and demonstrate that they act downstream of Tiam1. We also show that depletion of Pak1/2 allows cells to escape monopolar arrest by Eg5 inhibition, highlighting the potential importance of this signalling pathway for the development of Eg5 inhibitors as cancer therapeutics. Centrosome separation, promoted by the kinesin Eg5, is antagonized by the guanine nucleotide exchange factor Tiam1 through an unknown mechanism. Here Whalley et al. show that Tiam1 is phosphorylated by cyclin-dependent kinase 1 in prophase, leading to downstream activation of p21-activated kinases (PAKs).
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影响因子：
4.8
作者：
Buchsbaum, RJ;Connolly, BA;Feig, LA
通讯作者：
Feig, LA
影响因子：
9.2
作者：
Mardin, Balca R.;Agircan, Fikret G.;Schiebel, Elmar
通讯作者：
Schiebel, Elmar
影响因子：
11.2
作者：
Chow HY;Jubb AM;Koch JN;Jaffer ZM;Stepanova D;Campbell DA;Duron SG;O'Farrell M;Cai KQ;Klein-Szanto AJ;Gutkind JS;Hoeflich KP;Chernoff J
通讯作者：
Chernoff J
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L
影响因子：
5.3
作者：
Buchsbaum, RJ;Connolly, BA;Feig, LA
通讯作者：
Feig, LA