Oncoprotein YAP Regulates the Spindle Checkpoint Activation in a Mitotic Phosphorylation-dependent Manner through Up-regulation of BubR1

• Published in: The Journal of biological chemistry 2015-03, Vol.290 (10), p.6191-6202
• Main Authors: Yang, Shuping, Zhang, Lin, Chen, Xingcheng, Chen, Yuanhong, Dong, Jixin
• Format: Article
• Language: English
• Subjects: BubR1; Cell Cycle Proteins; Dual-Specificity Phosphatases - metabolism; Gene Expression Regulation; Hippo Pathway; Humans; M Phase Cell Cycle Checkpoints - genetics; MCF-7 Cells; Mitosis; Neoplasms - genetics; Neoplasms - pathology; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oncogene; Phosphorylation; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction; Spindle Checkpoint; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription, Genetic; Yes-associated Protein (YAP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.624411

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. Background: Oncoprotein YAP regulates cell proliferation and tumorigenesis, and a cellular function of YAP in mitosis is largely unknown. Results: YAP and its mitotic phosphorylation regulate the spindle checkpoint through up-regulation of BubR1. Conclusion: The findings reveal a novel link between YAP and the spindle checkpoint. Significance: Our studies indicate a potential mechanism underlying the oncogenic function of YAP through dysregulation of the spindle checkpoint.