SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis
Open accessAbstract
Significance: We demonstrate a mechanism whereby germline mutations in MRAS, SHOC2, and PPP1CB contribute directly to Noonan syndrome by enhancing formation of a ternary complex, which specifically dephosphorylates an inhibitory site on RAF kinases, activating downstream signaling. SHOC2 is required for tumorigenic properties of tumor-derived cell lines with RAS mutations and has more recently been identified by others in a synthetic lethal screen as a gene essential for viability of RAS mutant but not RAS wild-type cells. A thorough analysis of this complex at the biochemical and structural level has demonstrated the remarkable ability of this complex to dictate specificity for RAF and suggests possible strategies to inhibit the complex as a way of targeting the RAS–ERK pathway.
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SHOC2 and PPP1CB encode interacting proteins that regulate the RAS-MAPK pathway, and pathogenic variants in these genes are associated with a Noonan-like syndrome.
“Two of these genes with highly recurrent de novo SNVs, SHOC2 and PPP1CB, encode interacting proteins that regulate the RAS-MAPK pathway, and pathogenic variants in these genes are associated with a Noonan-like syndrome27.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [27]
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- Authors
- Young, L. C., Hartig, N., Boned del Río, I., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., & Rodriguez-Viciana, P.
- Affiliations
- University College London (GB)
- University College London Cancer Institute, University College London, London WC1E 6DD, United Kingdom;
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-10-22
- Volume
- 115
- Issue
- 45
- Pages
- E10576-E10585
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6233131
- OpenAlex
- W2897444172
- Cited by
- 98
- References
- 59
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 16 · 2023: 17 · 2022: 14 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 1
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Cancer Research UK (S_3327)
- British Heart Foundation (FS/18/65/34186B)
- Rosetrees Trust (M190-F2)
- National Cancer Institute (R35CA197709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- SHOC2, mineralocorticoid receptor antagonists, protein phosphatase 1, Noonan syndrome, PPP1CB, ERK signaling, ternary complex formation, oncogenic Ras, RAS/MAPK pathway
- MeSH terms
- Carrier Proteins, Cell Line, Humans, Models, Molecular, Mutation, Noonan Syndrome, Phosphorylation, Sequence Alignment, ras Proteins, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, raf Kinases, Protein Phosphatase 1, HEK293 Cells
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