Related Experiment Video

Updated: Aug 27, 2025

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells
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Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

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Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome

Daniel A Bonsor1, Patrick Alexander1, Kelly Snead1

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

Nature Structural & Molecular Biology
|September 29, 2022
PubMed

Insights

SHOC2 protein forms a complex with MRAS and PP1C, enhancing RAF-MAPK pathway regulation. This structural insight into the SHOC2-MRAS-PP1C complex reveals therapeutic targets for KRAS cancers and Noonan syndrome.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • SHOC2 is a synthetic lethal interactor with MEK inhibitors in KRAS cancers.
  • SHOC2 regulates RAF and MAPK pathway activation through a complex with MRAS and PP1C.
  • This complex dephosphorylates RAF kinases, impacting cancer cell signaling.

Purpose of the Study:

  • To determine the high-resolution crystal structure of the SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2.
  • To elucidate the structural basis of SMP complex formation and its role in RAF activation.
  • To identify potential therapeutic interventions based on structural insights.

Main Methods:

  • X-ray crystallography to obtain high-resolution structures of the SMP complex and apo-SHOC2.
  • Biochemical assays to assess the dephosphorylation activity of the complex.
  • Structural analysis to understand protein-protein interactions within the complex.

Main Results:

  • The crystal structure reveals a stable ternary complex formed by SHOC2, MRAS, and PP1C with synergistic interactions.
  • Dephosphorylation of RAF substrates by PP1C is significantly enhanced within the SMP complex.
  • SMP complex formation is dependent on the active state of MRAS and SHOC2's scaffolding function.

Conclusions:

  • The SMP complex plays a crucial role in RAF activation, with SHOC2 acting as a scaffold.
  • Structural insights explain how Noonan syndrome mutations enhance SMP complex formation.
  • The study provides a foundation for developing novel therapeutic strategies targeting the SMP complex in cancer and genetic disorders.

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