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Eyes Absent 家族成员 EYA4 和 EYA1 通过酪氨酸去磷酸化促进 PLK1 的激活和有丝分裂的顺利进行。

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation.

机构信息

Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, Australia.

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

出版信息

Nat Commun. 2024 Feb 15;15(1):1385. doi: 10.1038/s41467-024-45683-4.

DOI:10.1038/s41467-024-45683-4
PMID:38360978
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10869800/
Abstract

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis.

摘要

眼缺失蛋白（EYA1-4）是一组生化上独特的酪氨酸磷酸酶，已知在多种癌症类型中具有促进肿瘤的作用。迄今为止，EYA 磷酸酶活性的靶标在很大程度上仍未被描述。在这里，我们确定 Polo 样激酶 1（PLK1）是 EYA4 和 EYA1 的相互作用蛋白和磷酸酶底物，PLK1 上的 pY445 是主要的靶位。在细胞周期的 G2 期，pY445 的去磷酸化对于中心体成熟、PLK1 定位于中心体以及依赖于 polo 框结构域（PBD）的 PLK1 和 PLK1 激活复合物之间的相互作用是必需的。分子动力学模拟支持这样一种观点，即 pY445 赋予 PBD-底物相互作用结构上的损害，这种损害可以通过 EYA 介导的去磷酸化得到缓解。EYA4 或 EYA1 的耗竭，或 EYA 磷酸酶活性的化学抑制，显著降低 PLK1 的激活，导致有丝分裂缺陷和细胞死亡。总的来说，我们已经描述了一个调控 PLK1 和有丝分裂的磷酸酪氨酸信号网络。

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