Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton
Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton
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DOI：
10.1158/0008-5472.can-16-2060
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Swallow, Carol J.
中科院分区：
文献类型：
--
作者：
Kazazian, Karineh;Go, Christopher;Swallow, Carol J.
基于 polo 家族丝氨酸苏氨酸激酶 Plk4 在原发性人类癌症中的表达增加、在小鼠异种移植模型中促进肿瘤生长以及其过度表达诱导的中心体扩增，已提议将其作为晚期癌症的治疗靶点。然而，这些现象之间的因果关系和选择性 Plk4 抑制的可行性仍不清楚。在这里，我们描述了 Plk4 依赖性癌细胞迁移和侵袭以及癌症异种移植物的局部侵袭和转移。 Plk4 耗竭可抑制癌症侵袭并诱导低分化乳腺癌细胞出现上皮表型。在对 Plk4 相互作用子的无偏 BioID 筛选中，我们鉴定了 Arp2/3 复合体的成员，并证实了 Plk4 和 Arp2 之间在介导 Plk4 驱动的癌细胞运动中的物理和功能相互作用。这种相互作用是通过 Plk4 Polo-box 1-Polo-box 2 结构域介导的，导致 Arp2 在 T237/T238 激活位点磷酸化，这是 Plk4 驱动的细胞运动所必需的。我们的结果验证了 Plk4 作为癌症患者的治疗靶点，并揭示了 Plk4 在调节 Arp2/3 介导的肌动蛋白细胞骨架重排中的新作用。 (C) 2016 年 AACR。
The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts. Plk4 depletion suppressed cancer invasion and induced an epithelial phenotype in poorly differentiated breast cancer cells. In an unbiased BioID screen for Plk4 interactors, we identified members of the Arp2/3 complex and confirmed a physical and functional interaction between Plk4 and Arp2 in mediating Plk4-driven cancer cell movement. This interaction is mediated through the Plk4 Polo-box 1-Polo-box 2 domain and results in phosphorylation of Arp2 at the T237/T238 activation site, which is required for Plk4-driven cell movement. Our results validate Plk4 as a therapeutic target in cancer patients and reveal a new role for Plk4 in regulating Arp2/3-mediated actin cytoskeletal rearrangement. (C) 2016 AACR.