title: Oncoprotein YAP regulates the spindle checkpoint activation in a mitotic phosphorylation-dependent manner through up-regulation of BubR1.
abstract: The transcriptional co-activator YAP (Yes-associated protein) functions as an oncogene; however, it is largely unclear how YAP exerts its oncogenic role. In this study, we further explored the functional significance of YAP and its mitotic phosphorylation in the spindle checkpoint. We found that the dynamic mitotic phosphorylation of YAP was CDC14-dependent. We also showed that YAP was required for the spindle checkpoint activation induced by spindle poisons. Mitotic phosphorylation of YAP was required for activation of the spindle checkpoint. Furthermore, enhanced expression of active YAP hyperactivated the spindle checkpoint and induced mitotic defects in a mitotic phosphorylation-dependent manner. Mechanistically, we documented that mitotic phosphorylation of YAP controlled transcription of genes associated with the spindle checkpoint. YAP constitutively associated with BubR1 (BUB1-related protein kinase), and knockdown of BubR1 relieved YAP-driven hyperactivation of the spindle checkpoint. Finally, we demonstrated that YAP promoted epithelial cell invasion via both mitotic phosphorylation and BubR1-dependent mechanisms. Together, our results reveal a novel link between YAP and the spindle checkpoint and indicate a potential mechanism underlying the oncogenic function of YAP through dysregulation of the spindle checkpoint.
authors.affiliation: From the Department of Oncology, Shandong Provincial Hospital affiliated with Shandong University, Jinan, Shandong 250021, China and the Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.affiliation: the Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Chen
authors.affiliation: the Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: the Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198 dongj@unmc.edu.
authors.forename: Jixin
authors.initials: J
authors.lastname: Dong
mesh_terms: D018797:Cell Cycle Proteins; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; C474200:CDC14B protein, human; D054637:Dual-Specificity Phosphatases
keywords: BubR1; Hippo Pathway; Mitosis; Oncogene; Phosphorylation; Spindle Checkpoint; Yes-associated Protein (YAP)