A novel role for Plk4 in regulating cell spreading and motility
A novel role for Plk4 in regulating cell spreading and motility
复制标题
DOI：
10.1038/onc.2014.275
复制
发表时间：
2015-06-01
期刊：
影响因子：
8
通讯作者：
Swallow, C. J.
中科院分区：
文献类型：
--
作者：
Rosario, C. O.;Kazazian, K.;Swallow, C. J.
Polo 家族激酶 4 (Plk4) 是有丝分裂进展所必需的，并且单倍体不足以抑制肿瘤抑制和再生肝脏中及时的肝细胞极化。与此同时，最近的证据表明 Plk4 表达可能在临床癌症进展中发挥作用，尽管其机制尚不清楚。在这里，我们确定了预测 Plk4(+/-) 小鼠胚胎成纤维细胞 (MEF) 运动性降低的基因表达模式，并通过细胞扩散、迁移和侵袭的功能分析验证了这一预测。 Plk4 表达增加可增强 Plk4(+/-) MEF 中的细胞扩散和人胚肾 293T 细胞中的迁移，并增加 DLD-1 结肠癌细胞的侵袭。 Plk4 耗竭会损害野生型 MEF 的侵袭并抑制 MDA-MB231 乳腺癌细胞的侵袭。在受到刺激迁移的 Plk4 缺陷细胞中，细胞骨架重组和极性发展受到损害。在自磷酸化位点 S305 磷酸化的内源性 Plk4 定位于运动细胞的突起，与 RhoA GEF Ect2、GTP 结合的 RhoA 和 RhoA 效应子 mDia 一致。总而言之，我们的研究结果揭示了 Plk4 的一种意想不到的活性，它可以促进细胞迁移，并可能是实体瘤患者中 Plk4 表达增加、癌症进展和转移死亡之间存在关联的基础。
Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4(+/-) murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4(+/-) MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.