title: CDK1 phosphorylation of TAZ in mitosis inhibits its oncogenic activity.
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.
authors.affiliation: Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China.|Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Stauffer
authors.affiliation: Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Eppley Institute for Research in Cancer, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
mesh_terms: D000217:Acyltransferases; D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008938:Mitosis / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
keywords: CDK1; Hippo pathway; TAZ; mitotic defects; mitotic phosphorylation