Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
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Significance: Rat sarcoma (Ras) proteins play central roles in both normal and oncogenic signaling. Mechanisms of how Ras interacts with its effectors on the cell membrane, however, are still poorly understood, significantly hampering efforts to target this molecule in human cancer. Here we have used quantitative superresolution fluorescence microscopy in combination with carefully engineered biological systems to show that Ras dimers drive oncogenic signaling through the Raf-MAPK pathway. Our study suggests a new, dimer model of Ras-Raf signaling and the potential value of Ras dimers as a therapeutic target.
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KRAS monomers undergo dimerization for their downstream signaling activity.
“More recent evidence suggests that KRAS monomers undergo dimerization for their downstream signaling activity [21].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [21]
The altered dynamics may cause a conformational change of KRAS on the membrane, resulting in occluded conformation from a specific effector, alter dimer formation, or affect KRAS nanoclustering.
“The altered dynamics may cause a conformational change of KRAS on the membrane, resulting in occluded conformation from a specific effector [23], alter the dimer formation [64], or affect KRAS nanoclustering [65].”
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- [23]Rajakulendran T, Sahmi M, Lefrançois M, Sicheri F, Therrien M (2009) A dimerizationdependent mechanism drives RAF catalytic activation. Nature 461(7263):542 -545.
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- Authors
- Nan, X., Tamgüney, T. M., Collisson, E. A., Lin, L.-J., Pitt, C., Galeas, J., Lewis, S., Gray, J. W., McCormick, F., & Chu, S.
- Affiliations
- QB3 (US)
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Oregon Health & Science University (US)
- Stanford University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-16
- Volume
- 112
- Issue
- 26
- Pages
- 7996-8001
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4491781
- OpenAlex
- W1492513673
- Cited by
- 273
- References
- 42
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 20 · 2023: 23 · 2022: 19 · 2021: 38 · 2020: 30 · 2019: 23 · 2018: 30 · 2017: 27 · 2016: 30 · 2015: 9
- FWCI
- 13.90
- 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)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | National Institutes of Health (K08 CA137153, 5U54CA143836, NIH U54 CA112970)
- National Science Foundation (PHY- 0647161)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- Ras GTPase, MAPK signaling, KRAS G12D, MAPK/ERK pathway, CAAX motif, membrane localization, therapeutic target
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Guanosine Triphosphate, Cricetinae, ras Proteins, Dimerization, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System
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