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RAS interaction with Sin1 is dispensable for mTORC2 assembly and activity

  1. Author:
    Castel, Pau [ORCID]
    Dharmaiah,Sathiya
    Sale, Matthew J
    Messing,Simon [ORCID]
    Rizzuto, Gabrielle [ORCID]
    Cuevas-Navarro, Antonio [ORCID]
    Cheng, Alice
    Trnka, Michael J [ORCID]
    Urisman, Anatoly [ORCID]
    Esposito,Dom [ORCID]
    Simanshu,Dhirendra [ORCID]
    McCormick, Frank [ORCID]

  2. Author Address

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158., National Cancer Institute (NCI) RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702., Department of Anatomic Pathology, University of California, San Francisco, CA 94158., Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158., National Cancer Institute (NCI) RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; Frank.mccormick@ucsf.edu dhirendra.simanshu@nih.gov., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158; Frank.mccormick@ucsf.edu dhirendra.simanshu@nih.gov.,
    1. Year: 2021
    2. Date: Aug 17
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 118
    2. 33
  4. Type of Article: Article
  5. Article Number: e2103261118
  6. ISSN: 0027-8424
  1. Abstract:

    RAS proteins are molecular switches that interact with effector proteins when bound to guanosine triphosphate, stimulating downstream signaling in response to multiple stimuli. Although several canonical downstream effectors have been extensively studied and tested as potential targets for RAS-driven cancers, many of these remain poorly characterized. In this study, we undertook a biochemical and structural approach to further study the role of Sin1 as a RAS effector. Sin1 interacted predominantly with KRAS isoform 4A in cells through an atypical RAS-binding domain that we have characterized by X-ray crystallography. Despite the essential role of Sin1 in the assembly and activity of mTORC2, we find that the interaction with RAS is not required for these functions. Cells and mice expressing a mutant of Sin1 that is unable to bind RAS are proficient for activation and assembly of mTORC2. Our results suggest that Sin1 is a bona fide RAS effector that regulates downstream signaling in an mTORC2-independent manner.

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External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.2103261118
  3. PMID: 34380736
  4. View record in Web of Science®
  5. WOS: 000687404200018
  6. PII : 2103261118

Library Notes

  1. Fiscal Year: FY2020-2021
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