CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity

Abstract

// Lin Zhang 1, 2 , Xingcheng Chen 2 , Seth Stauffer 2 , Shuping Yang 3 , Yuanhong Chen 2 , Jixin Dong 2 1 Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China 2 Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA 3 Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P.R. China Correspondence to: Jixin Dong, e-mail: dongj@unmc.edu Keywords: TAZ, Hippo pathway, mitotic phosphorylation, CDK1, mitotic defects Received: June 30, 2015      Accepted: August 26, 2015      Published: September 07, 2015 ABSTRACT 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.