CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity
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Lin Zhang1,2, Xingcheng Chen2, Seth Stauffer2, Shuping Yang3, Yuanhong Chen2, Jixin Dong2
1Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
2Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
3Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P.R. China
Jixin Dong, e-mail: [email protected]
Keywords: TAZ, Hippo pathway, mitotic phosphorylation, CDK1, mitotic defects
Received: June 30, 2015 Accepted: August 26, 2015 Published: September 07, 2015
The transcriptional co-activator with PDZ-binding motif (TAZ) is a downstream effector of the Hippo tumor suppressor pathway, which plays important roles in cancer and stem cell biology. Hippo signaling inactivates TAZ through phosphorylation (mainly at S89). In the current study, we define a new layer of regulation of TAZ activity that is critical for its oncogenic function. We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity, as the non-phosphorylatable mutant (TAZ-S89A/S90A/S105A/T326A/T346A, TAZ-5A) possesses higher activity in epithelial-mesenchymal transition, anchorage-independent growth, cell migration, and invasion when compared to the TAZ-S89A mutant. Accordingly, TAZ-5A has higher transcriptional activity compared to the TAZ-S89A mutant. Finally, we show that TAZ-S89A or TAZ-5A (to a greater extent) was sufficient to induce spindle and centrosome defects, and chromosome misalignment/missegregation in immortalized epithelial cells. Together, our results reveal a previously unrecognized connection between TAZ oncogenicity and mitotic phospho-regulation.
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