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The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2
Open accessAbstract
Proximity-dependent biotin labeling (BioID) may identify new targets for cancers driven by difficult-to-drug oncogenes such as Ras. Therefore, BioID was used with wild-type (WT) and oncogenic mutant (MT) H-, K-, and N-Ras, identifying known interactors, including Raf and PI3K, as well as a common set of 130 novel proteins proximal to all Ras isoforms. A CRISPR screen of these proteins for Ras dependence identified mTOR, which was also found proximal to MT Ras in human tumors. Oncogenic Ras directly bound two mTOR complex 2 (mTORC2) components, mTOR and MAPKAP1, to promote mTORC2 kinase activity at the plasma membrane. mTORC2 enabled the Ras pro-proliferative cell cycle transcriptional program, and perturbing the Ras-mTORC2 interaction impaired Ras-dependent neoplasia in vivo. Combining proximity-dependent proteomics with CRISPR screening identified a new set of functional Ras-associated proteins, defined mTORC2 as a new direct Ras effector, and offers a strategy for finding new proteins that cooperate with dominant oncogenes.
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“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [16]
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“four interact with or signal through KRAS16,38 or are known oncogenes or tumor suppressors39: TP53, RNF43, MAP2K4, and RBM10”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [16]
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Metadata
- Authors
- Kovalski, J. R., Bhaduri, A., Zehnder, A. M., Neela, P. H., Che, Y., Wozniak, G. G., & Khavari, P. A.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Stanford University (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Khavari, Paul A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 73
- Issue
- 4
- Pages
- 830-844.e12
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6386588
- OpenAlex
- W2909177041
- Cited by
- 154
- References
- 60
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 16 · 2023: 25 · 2022: 23 · 2021: 27 · 2020: 22 · 2019: 9
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Veterans Affairs
- NIH (AR43799, CA142635)
- National Center Research Resources (P30 CA124435, S10RR027425)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- oncogenic Ras, mTORC2, mTOR, Raf, phosphatidylinositol 3-kinase, CRISPR screen, Ras isoforms
- MeSH terms
- Mechanistic Target of Rapamycin Complex 2, Animals, Binding Sites, Cell Transformation, Neoplastic, Female, Humans, Mice, Hairless, Mice, Transgenic, Mutation, Neoplasms, Protein Binding, Gene Expression Regulation, Neoplastic, Mice, SCID, ras Proteins, Caco-2 Cells, Proteome, Proteomics, Tumor Burden, Cell Proliferation, Protein Interaction Domains and Motifs, HEK293 Cells, Cell Cycle Checkpoints, CRISPR-Cas Systems
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