The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.

Autor:	Kovalski JR; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA; Program in Cancer Biology, Stanford University, Stanford, CA 94305, USA., Bhaduri A; The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94131, USA., Zehnder AM; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA., Neela PH; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA., Che Y; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA; Program in Cancer Biology, Stanford University, Stanford, CA 94305, USA., Wozniak GG; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA., Khavari PA; Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA; Program in Cancer Biology, Stanford University, Stanford, CA 94305, USA; VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA. Electronic address: khavari@stanford.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2019 Feb 21; Vol. 73 (4), pp. 830-844.e12. Date of Electronic Publication: 2019 Jan 10.
DOI:	10.1016/j.molcel.2018.12.001
Abstrakt:	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. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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