Related Experiment Video

Updated: Aug 2, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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Structural insights into the role of SHOC2-MRAS-PP1C complex in RAF activation

Daniel A Bonsor1, Dhirendra K Simanshu1

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Maryland, USA.

The FEBS Journal
|April 19, 2023
PubMed

Insights

The SHOC2-MRAS-PP1C complex activates RAF kinases, crucial for MAPK signaling. Understanding its structure and function offers new therapeutic targets for RASopathies and cancers.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • RAF activation is central to the mitogen-activated protein kinase (MAPK) pathway.
  • The SHOC2 protein, alongside MRAS and protein phosphatase 1 catalytic subunit (PP1C), forms a holoenzyme that activates RAF kinases.
  • Recent studies have provided significant structural and functional insights into this SHOC2-MRAS-PP1C (SMP) holoenzyme complex.

Approach:

  • Reviewing recent structural and functional data on the SMP complex.
  • Analyzing SMP complex assembly and the role of MRAS nucleotide-bound states.
  • Investigating the substitution of MRAS by canonical RAS proteins.
  • Examining the contributions of SHOC2 and MRAS to PP1C activity and specificity.

Key Points:

  • The SMP complex's assembly is dependent on the nucleotide-bound state of MRAS.
  • SHOC2 and MRAS modulate the activity and specificity of PP1C.
  • RASopathy-associated mutations within the SMP complex are discussed.
  • Potential therapeutic strategies targeting the SMP complex for RAS/RAF-driven diseases are explored.

Conclusions:

  • The SMP complex is a critical regulator of RAF activation within the MAPK pathway.
  • Structural and functional insights into the SMP complex pave the way for targeted therapies.
  • Understanding the SMP complex's role in RASopathies and cancers is essential for developing novel treatments.
Keywords:
PP1CRAFRASRASopathySHOC2

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