Journal
MOLECULAR CELL
Volume 73, Issue 4, Pages 830-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.12.001
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Funding
- Veterans Affairs Office of Research and Development
- NIH [AR43799, CA142635]
- NIH/National Center Research Resources [P30 CA124435, S10RR027425]
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Proximity-dependent biotin labeling (BiolD) may identify new targets for cancers driven by difficult-to-drug oncogenes such as Ras. Therefore, BiolD 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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