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.

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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