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Updated: Mar 19, 2026

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

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TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

Dafni-Eleftheria Pefani1, Daniela Pankova1, Aswin G Abraham1

  • 1CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.

Molecular Cell
|June 14, 2016
PubMed

Insights

Transforming growth factor-beta (TGF-β) triggers the degradation of RASSF1A via the ubiquitin-proteasome pathway. This degradation is crucial for YAP1/SMAD2 interaction and TGF-β-induced gene transcription, impacting tumor suppression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Epigenetic inactivation of RASSF1A is linked to poor cancer prognosis and reduced tumor suppressor activity.
  • The protein-level regulation of RASSF1A, a key Hippo pathway scaffold, remains largely unknown.
  • Understanding RASSF1A regulation is critical for elucidating its role in cancer development.

Purpose of the Study:

  • To identify the physiological signal regulating RASSF1A protein degradation.
  • To elucidate the mechanism by which RASSF1A protein levels are controlled.
  • To investigate the functional consequences of RASSF1A degradation on cancer-related signaling pathways.

Main Methods:

  • Investigated the role of transforming growth factor-beta (TGF-β) in RASSF1A regulation.
  • Utilized ubiquitin-proteasome pathway assays to study RASSF1A degradation.
  • Examined the interaction between RASSF1A, TGF-β receptor I, and the E3 ubiquitin ligase ITCH.
  • Assessed the impact of RASSF1A degradation on Hippo pathway effectors YAP1 and SMAD2.
  • Analyzed the effects on TGF-β-induced gene transcription and cellular invasion.

Main Results:

  • TGF-β was identified as the physiological signal inducing RASSF1A degradation via the ubiquitin-proteasome pathway.
  • RASSF1A is recruited to TGF-β receptor I and targeted for degradation by the E3 ubiquitin ligase ITCH.
  • RASSF1A degradation is essential for YAP1 to associate with SMADs and for SMAD2 nuclear translocation.
  • RASSF1A regulates TGF-β-induced YAP1/SMAD2 interaction, SMAD2 cytoplasmic retention, and inefficient transcription of TGF-β target genes.
  • RASSF1A limits TGF-β-induced invasion, highlighting its tumor-suppressive function.

Conclusions:

  • TGF-β-induced RASSF1A degradation is a key regulatory mechanism controlling the Hippo pathway and TGF-β signaling.
  • RASSF1A acts as a negative regulator of TGF-β-induced YAP1/SMAD2 signaling and invasion.
  • This study provides a novel framework for understanding RASSF1A's tumor-suppressive functions through modulation of YAP1 transcriptional output.

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