CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transformation

Shuping Yang, Lin Zhang, Miao Liu, Rong Chong, Shi Jian Ding, Yuanhong Chen, Jixin Dong

Research output: Contribution to journalArticle

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Abstract

The Yes-associated protein, YAP, is a downstream effector of the Hippo pathway of cell-cycle control that plays important roles in tumorigenesis. Hippo-mediated phosphorylation YAP, mainly at S127, inactivates YAP function. In this study, we define a mechanism for positive regulation of YAP activity that is critical for its oncogenic function. Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell-cycle kinase CDK1 at T119, S289, and S367 during the G2-M phase of the cell cycle. We also found that ectopic expression of a phosphomimetic YAP mutant (YAP3D, harboring T119D/S289D/S367D) was sufficient to induce mitotic defects in immortalized epithelial cells, including centrosome amplification, multipolar spindles, and chromosome missegregation. Finally, we documented that mitotic phosphorylation of YAP was sufficient to promote cell migration and invasion in a manner essential for neoplastic cell transformation. In support of our findings, CDK1 inhibitors largely suppressed cell motility mediated by activated YAP-S127A but not the phosphomimetic mutant YAP3D. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YAP that is crucial for its oncogenic function mediated by mitotic dysregulation.

Original languageEnglish (US)
Pages (from-to)6722-6733
Number of pages12
JournalCancer Research
Volume73
Issue number22
DOIs
StatePublished - Nov 15 2013

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Cell Movement
Cell Cycle
Neoplastic Cell Transformation
Phosphorylation
Centrosome
G2 Phase
Cell Cycle Checkpoints
Cell Division
Carcinogenesis
Phosphotransferases
Chromosomes
Epithelial Cells
Proteins
In Vitro Techniques
Ectopic Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transformation. / Yang, Shuping; Zhang, Lin; Liu, Miao; Chong, Rong; Ding, Shi Jian; Chen, Yuanhong; Dong, Jixin.

In: Cancer Research, Vol. 73, No. 22, 15.11.2013, p. 6722-6733.

Research output: Contribution to journalArticle

Yang, Shuping ; Zhang, Lin ; Liu, Miao ; Chong, Rong ; Ding, Shi Jian ; Chen, Yuanhong ; Dong, Jixin. / CDK1 phosphorylation of YAP promotes mitotic defects and cell motility and is essential for neoplastic transformation. In: Cancer Research. 2013 ; Vol. 73, No. 22. pp. 6722-6733.
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AU - Dong, Jixin

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