NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

Area of Science:

• Cell Biology
• Molecular Biology
• Oncology

Background:

• The Hippo signaling pathway is crucial for organ size control, tumor suppression, and cell proliferation in mammals.
• While activators of Hippo signaling are known, antagonists remain largely undiscovered.
• Mutations in NPHP4 cause nephronophthisis, a severe kidney disease.

Purpose of the Study:

• To identify antagonists of the mammalian Hippo signaling pathway.
• To investigate the role of NPHP4 in regulating Hippo signaling and cell proliferation.

Main Methods:

• Investigated NPHP4's interaction with Lats1 kinase.
• Assessed Lats1-mediated phosphorylation of YAP and TAZ.
• Analyzed NPHP4's effect on YAP/TAZ binding to 14-3-3 proteins and nuclear translocation.
• Examined NPHP4's impact on TEAD/TAZ/YAP-dependent transcription and cellular proliferation via knockdown experiments.

Main Results:

• NPHP4 directly interacts with and inhibits Lats1 kinase.
• NPHP4 prevents Lats1-mediated phosphorylation of YAP and TAZ, leading to their derepression.
• NPHP4 promotes YAP and TAZ release from 14-3-3 binding and enhances their nuclear translocation.
• NPHP4 knockdown impairs cellular proliferation and TEAD/TAZ activity, mimicking TAZ loss.

Conclusions:

• NPHP4 functions as a potent negative regulator of the mammalian Hippo signaling pathway.
• NPHP4 controls cell proliferation through its modulation of Hippo signaling, specifically impacting YAP and TAZ activity.