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Updated: Sep 12, 2025

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Type I gamma phosphatidylinositol phosphate kinase i5 suppresses YAP1 signaling

Chinmoy Ghosh1, Ruchi Kakar1, Matthew Bavuso1

  • 1Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, Virginia, USA.

The Journal of Biological Chemistry
|August 10, 2025
PubMed

Insights

Type I gamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5) suppresses Yes-associated protein 1 (YAP1) signaling by producing PI4,5P2, which retains YAP1 in the cytosol. PIPKIγi5 depletion enhances YAP1 signaling and tumor formation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Hippo/Yes-associated protein (YAP) signaling pathway dysregulation is linked to diseases like cancer.
  • The molecular mechanisms and regulators of Hippo/YAP signaling are not fully understood.
  • Identifying novel regulators is crucial for understanding disease pathogenesis.

Purpose of the Study:

  • To identify novel regulators of the Hippo/YAP signaling pathway.
  • To elucidate the role of type I gamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5) in YAP1 signaling.
  • To investigate the impact of PIPKIγi5 on cancer cell stemness.

Main Methods:

  • Investigated the interaction between PIPKIγi5 and YAP1.
  • Assessed the effect of PIPKIγi5 kinase activity on YAP1 nuclear translocation.
  • Utilized head and neck squamous cell carcinoma models to study tumorsphere formation.

Main Results:

  • PIPKIγi5 directly interacts with YAP1, preventing its nuclear translocation and suppressing YAP1-mediated transcription.
  • The kinase activity of PIPKIγi5, generating phosphatidylinositol-4,5-bisphosphate (PI4,5P2), is essential for this suppression.
  • PI4,5P2 promotes YAP1 interaction with 14-3-3 protein, retaining YAP1 in the cytosol.
  • Depletion of PIPKIγi5 enhances YAP1 signaling and promotes tumorsphere formation in head and neck squamous cell carcinoma.

Conclusions:

  • PIPKIγi5 acts as a suppressor of YAP1-mediated signaling through PI4,5P2 production.
  • This PI4,5P2-modulated signaling nexus provides specific control over Hippo/YAP signaling.
  • PIPKIγi5 is a critical regulator of YAP1 function and has implications in cancer stemness.
Keywords:
14-3-3PI4,5P(2)PIPKIγi5YAP1tumorsphere

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