NMR-based functional profiling of RASopathies and oncogenic RAS mutations
Open accessAbstract
Defects in the RAS small G protein or its associated network of regulatory proteins that disrupt GTPase cycling are a major cause of cancer and developmental RASopathy disorders. Lack of robust functional assays has been a major hurdle in RAS pathway-targeted drug development. We used NMR to obtain detailed mechanistic data on RAS cycling defects conferred by oncogenic mutations, or full-length RASopathy-derived regulatory proteins. By monitoring the conformation of wild-type and oncogenic RAS in real-time, we show that opposing properties integrate with regulators to hyperactivate oncogenic RAS mutants. Q61L and G13D exhibited rapid nucleotide exchange and an unexpected susceptibility to GAP-mediated hydrolysis, in direct contrast with G12V, indicating different approaches must be taken to inhibit these oncoproteins. An NMR methodology was established to directly monitor RAS cycling by intact, multidomain proteins encoded by RASopathy genes in mammalian cell extracts. By measuring GAP activity from tumor cells, we demonstrate how loss of neurofibromatosis type 1 (NF1) increases RAS-GTP levels in NF1-derived cells. We further applied this methodology to profile Noonan Syndrome (NS)-derived SOS1 mutants. Combining NMR with cell-based assays allowed us to differentiate defects in catalysis, allosteric regulation, and membrane targeting of individual mutants, while revealing a membrane-dependent compensatory effect that attenuates dramatic increases in RAS activation shown by Y337C, L550P, and I252T. Our NMR method presents a precise and robust measure of RAS activity, providing mechanistic insights that facilitate discovery of therapeutics targeted against the RAS signaling network.
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Mutations to codons 12, 13, and 61 reduce the rate of intrinsic and/or GAP-mediated hydrolysis.
“mutations to codons 12, 13, and 61 reduce the rate of intrinsic and/or GAP-mediated hydrolysis”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [9]
Mutations at codons 13 and 61, but not 12, also enhance the rate of nucleotide exchange.
“mutations at 13 and 61, but not 12, also enhance the rate of nucleotide exchange8,9”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [9]
Activating KRAS mutations result in elevated engagement of downstream pathways by increasing the steady-state levels of GTP-bound KRAS.
“Activating KRAS mutations result in elevated engagement of downstream pathways by increasing the steady-state levels of GTP-bound KRAS.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [9]
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BackgroundIntegrated RAS signaling defined by parallel NMR detection of effectors and regulators
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Data from Delineating the RAS Conformational Landscape
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- Authors
- Smith, M. J., Neel, B. G., & Ikura, M.
- Affiliations
- Campbell Family Cancer Research Institute, Ontario Cancer Institute, and
- University of Toronto (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-03-04
- Volume
- 110
- Issue
- 12
- Pages
- 4574-4579
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3607025
- OpenAlex
- W2004731962
- Cited by
- 257
- References
- 44
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 16 · 2023: 23 · 2022: 28 · 2021: 31 · 2020: 34 · 2019: 26 · 2018: 11 · 2017: 15 · 2016: 15 · 2015: 10 · 2014: 9 · 2013: 5
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Society
- Princess Margaret Hospital Foundation
- Ontario Ministry of Health and Long-Term Care
- Canada Research Chairs
- National Institutes of Health
- National Cancer Institute (R37-CA49132)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- RASopathies, oncogenic Ras mutations, GTPase-activating protein, nucleotide exchange, SOS1, Noonan syndrome, neurofibromatosis type 1, allosteric regulation, membrane targeting, Ras signaling
- MeSH terms
- Enzyme Activation, Humans, Neoplasms, Neurofibromatosis 1, Signal Transduction, Oncogene Protein p21(ras), Nuclear Magnetic Resonance, Biomolecular, Amino Acid Substitution, Mutation, Missense, Cell Line, Tumor, HEK293 Cells
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