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Updated: Dec 6, 2025

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

Published on: September 13, 2018

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RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

Thillaivillalan Dhanaraman1, Swati Singh1, Ryan C Killoran1

  • 1Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.

Science Signaling
|October 14, 2020
PubMed

Insights

This study reveals how RAS effector proteins (RASSFs) interact with various RAS GTPases, impacting cell signaling pathways like Hippo and p53. These interactions are crucial for understanding cancer and cell death regulation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Small GTPases of the RAS superfamily are key regulators of cell signaling.
  • RAS-association (RA) domains define effector proteins that bind activated RAS.
  • The binding specificities of most RA domains across the RAS superfamily are largely uncharacterized.

Purpose of the Study:

  • To characterize the binding specificities of RA domain family (RASSF) proteins with RAS GTPases.
  • To elucidate the role of RASSFs in coupling RAS signaling to the Hippo and p53 pathways.
  • To investigate the structural basis for RASSF-GTPase interaction specificity.

Main Methods:

  • Protein complex formation assays (e.g., co-immunoprecipitation).
  • Structural modeling and analysis of RASSF proteins.
  • GTPase binding assays.
  • YAP1 nuclear localization studies.

Main Results:

  • RASSF1-6 associated with MST1 (Hippo pathway kinase), while RASSF7-10 oligomerized with ASPP1/ASPP2 (p53 regulators).
  • Only RASSF5 directly bound activated HRAS and KRAS; RASSFs did not enhance RAS-induced apoptosis.
  • Structural modeling indicated evolutionary changes in RASSF residues dictate GTPase specificity.
  • RASSF1A interacted with GEM, REM1, REM2, and RASL12; RASSF-GTPase interactions inhibited YAP1 nuclear localization.

Conclusions:

  • RASSF proteins act as versatile scaffolds linking diverse RAS GTPases to either the Hippo or p53 pathways.
  • Evolutionary adaptations in RASSFs have refined their specificity for different RAS GTPases.
  • These interactions play a significant role in regulating YAP1 localization and potentially cell fate decisions.

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