Related Experiment Video

Updated: Jun 13, 2025

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
07:16

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

19.7K

Nuclear ubiquitination permits Hippo-YAP signal for liver development and tumorigenesis

Jinsong Wei1,2, Zhifa Cao1,3, Qing Li3

  • 1Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

Nature Chemical Biology
|May 16, 2025
PubMed

Insights

The E3 ligase UBR5 targets VGLL4 for degradation, activating Hippo-YAP signaling crucial for liver development and cancer. This discovery reveals nuclear ubiquitination as a potential therapeutic strategy for YAP-dependent cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

Background:

  • Hippo-YAP signaling regulates organ development and is implicated in tumorigenesis.
  • VGLL4 acts as a key transcriptional repressor by inhibiting YAP binding to TEAD transcription factors.

Purpose of the Study:

  • To identify the E3 ligase responsible for VGLL4 degradation.
  • To elucidate the role of the UBR5-VGLL4-YAP axis in liver development and human cancers.

Main Methods:

  • Identification of UBR5 as the E3 ligase for VGLL4 through ubiquitination assays.
  • Analysis of Ubr5 and Vgll4 expression patterns in mouse liver development.
  • Investigation of the UBR5-VGLL4-YAP axis in patient-derived tumor organoids.

Main Results:

  • UBR5 was identified as the nuclear E3 ligase that poly-ubiquitinates VGLL4 at Lys61, leading to its degradation.
  • Reciprocal expression of Ubr5 and Vgll4 was observed during mouse liver development.
  • Targeting nuclear E3 ligases inhibited the expansion of patient-derived tumor organoids.

Conclusions:

  • UBR5-mediated degradation of VGLL4 is a critical mechanism for regulating nuclear Hippo-YAP signaling.
  • The UBR5-VGLL4-YAP pathway is essential for liver biliary system development and is dysregulated in human pan-cancers.
  • Nuclear ubiquitination presents a promising therapeutic target for YAP-dependent malignancies.

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