Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198.
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6760-E6769. doi: 10.1073/pnas.1800621115. Epub 2018 Jul 2.
Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo-YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumorigenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.
锌指蛋白交联物（Zyxin）是黏着斑复合物的一个成员，在肌动蛋白丝聚合和细胞运动中发挥关键作用。最近的几项研究表明，Zyxin 是 Yes 相关蛋白（Yki/YAP）信号的正向调节因子。然而，关于 Zyxin 自身如何被调控以及 Zyxin 如何影响 Hippo-YAP 活性的机制知之甚少。我们首先表明，在有丝分裂期间，Zyxin 被 CDK1 磷酸化。Zyxin 耗竭导致结直肠癌细胞增殖、迁移、非锚定依赖性生长和异种移植动物模型中的肿瘤形成明显受损。有丝分裂磷酸化是 Zyxin 促进生长活性所必需的。Zyxin 通过结直肠癌细胞癌基因 CDK8 调节 YAP 活性。CDK8 敲除模拟了结直肠癌细胞中 Zyxin 敲低的表型，而 CDK8 的异位表达则显著恢复了 Zyxin 耗竭细胞的致瘤缺陷。在机制上，我们表明 CDK8 直接磷酸化 YAP 并促进其激活。完全激活的 YAP 是体外和体内 CDK8 敲除结直肠癌细胞生长所必需的。综上所述，这些观察结果表明，Zyxin 通过 CDK8 介导的 YAP 激活，以有丝分裂磷酸化依赖性的方式促进结直肠癌的肿瘤发生。
