Oncoprotein YAP regulates the spindle checkpoint activation in a mitotic phosphorylation-dependent manner through
Shuping Yang1, Lin Zhang2, Xingcheng Chen2
1From 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.
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.
Insights
Yes-associated protein (YAP) regulates the spindle checkpoint, a critical cell division process. YAP
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- The transcriptional co-activator YAP (Yes-associated protein) is recognized as an oncogene.
- The precise mechanisms through which YAP contributes to oncogenesis, particularly its role in cell division regulation, remain incompletely understood.
Purpose of the Study:
- To investigate the functional significance of YAP and its mitotic phosphorylation in the context of the spindle checkpoint.
- To elucidate the molecular mechanisms by which YAP influences spindle checkpoint activation and mitotic progression.
- To explore the role of YAP in promoting cancer progression, specifically epithelial cell invasion.
Main Methods:
- Investigated YAP's dynamic mitotic phosphorylation, identifying CDC14 dependence.
- Assessed YAP's requirement for spindle checkpoint activation by spindle poisons.
- Examined the impact of YAP expression levels and mitotic phosphorylation on spindle checkpoint activity and mitotic defects.
- Analyzed YAP's transcriptional control over spindle checkpoint genes and its interaction with BubR1 (BUB1-related protein kinase).
- Studied YAP's role in epithelial cell invasion through phosphorylation and BubR1-dependent pathways.
Main Results:
- YAP's dynamic mitotic phosphorylation is dependent on CDC14.
- YAP is essential for spindle checkpoint activation induced by spindle poisons, with mitotic phosphorylation being crucial.
- Enhanced expression of active YAP leads to hyperactivation of the spindle checkpoint and mitotic defects in a phosphorylation-dependent manner.
- Mitotic phosphorylation of YAP regulates the transcription of spindle checkpoint genes.
- YAP interacts with BubR1, and BubR1 knockdown mitigates YAP-induced spindle checkpoint hyperactivation.
- YAP promotes epithelial cell invasion via both mitotic phosphorylation and BubR1-dependent pathways.
Conclusions:
- This study reveals a novel functional link between YAP and the spindle checkpoint.
- YAP's oncogenic function may be mediated through the dysregulation of the spindle checkpoint.
- Mitotic phosphorylation of YAP and its interaction with BubR1 are key mechanisms underlying its role in cell division and invasion.
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