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

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.

• Authors: Shuping Yang, Lin Zhang, Miao Liu, Rong Chong, Shi-Jian Ding, Yuanhong Chen, Jixin Dong
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 22 Pg. 6722-33 (Nov 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 24101154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Nuclear Proteins
• Transcription Factors
• YY1AP1 protein, human
• CDC2 Protein Kinase
• Paclitaxel
• Nocodazole

Topics

• Antineoplastic Agents (pharmacology)
• Binding Sites (drug effects, genetics)
• CDC2 Protein Kinase (genetics, metabolism)
• Cell Cycle Proteins
• Cell Movement
• Cell Transformation, Neoplastic (genetics, metabolism)
• Cells, Cultured
• HCT116 Cells
• HEK293 Cells
• HeLa Cells
• Humans
• MCF-7 Cells
• Mitosis
• Nocodazole (pharmacology)
• Nuclear Proteins (chemistry, genetics, metabolism)
• Paclitaxel (pharmacology)
• Phosphorylation (drug effects)
• Transcription Factors (chemistry, genetics, metabolism)
• Up-Regulation (drug effects)