| Literature DB >> 29967145 |
Jiuli Zhou1,2,3, Yongji Zeng1,2,3, Lian Cui4, Xingcheng Chen1,2,3, Seth Stauffer1,2,3, Zhan Wang1,2, Fang Yu5, Subodh M Lele3, Geoffrey A Talmon3, Adrian R Black1,2, Yuanhong Chen1,2, Jixin Dong6,2.
Abstract
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.Entities:
Keywords: CDK8; Hippo–YAP pathway; Zyxin; colon cancer; mitosis
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Year: 2018 PMID： 29967145 PMCID： PMC6055133 DOI： 10.1073/pnas.1800621115
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205