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

  1. Author:
    Bonsor,Daniel
    Simanshu,Dhirendra [ORCID]

  2. Author Address

    NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.,
    1. Year: 2023
    2. Date: Apr 19
    3. Epub Date: 2023 04 19
  2. Journal: The FEBS Journal
  4. Type of Article: Article
  1. Abstract:

    RAF activation is a key step for signaling through the mitogen-activated protein kinase pathway. The SHOC2 protein, along with MRAS and PP1C, forms a high affinity, heterotrimeric holoenzyme that activates RAF kinases by dephosphorylating a specific phosphoserine. Recently, our research, along with that of three other teams, has uncovered valuable structural and functional insights into the SHOC2-MRAS-PP1C (SMP) holoenzyme complex. In this structural snapshot, we review SMP complex assembly, the dependency on the bound-nucleotide state of MRAS, the substitution of MRAS by the canonical RAS proteins, and the roles of SHOC2 and MRAS on PP1C activity and specificity. Furthermore, we discuss the effect of several RASopathy mutations identified within the SMP complex and explore potential therapeutic approaches for targeting the SMP complex in RAS/RAF-driven cancers and RASopathies. This article is protected by copyright. All rights reserved.

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External Sources

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  2. DOI: 10.1111/febs.16800
  3. PMID: 37074066

Library Notes

  1. Fiscal Year: FY2022-2023
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