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dc.contributor.authorPoulin, Emily J.
dc.contributor.authorBera, Asim K.
dc.contributor.authorLu, Jia
dc.contributor.authorLin, Yi-Jang
dc.contributor.authorStrasser, Samantha Dale
dc.contributor.authorPaulo, Joao A.
dc.contributor.authorHuang, Tannie Q.
dc.contributor.authorMorales, Carolina
dc.contributor.authorYan, Wei
dc.contributor.authorCook, Joshua
dc.contributor.authorNowak, Jonathan A.
dc.contributor.authorBrubaker, Douglas K.
dc.contributor.authorJoughin, Brian Alan
dc.contributor.authorJohnson, Christian W.
dc.contributor.authorDeStefanis, Rebecca A.
dc.contributor.authorGhazi, Phaedra C.
dc.contributor.authorGondi, Sudershan
dc.contributor.authorWales, Thomas E.
dc.contributor.authorIacob, Roxana E.
dc.contributor.authorBogdanova, Lana
dc.contributor.authorGierut, Jessica J.
dc.contributor.authorLi, Yina
dc.contributor.authorEngen, John R.
dc.contributor.authorPerez-Mancera, Pedro A.
dc.contributor.authorBraun, Benjamin S.
dc.contributor.authorGygi, Steven P.
dc.contributor.authorLauffenburger, Douglas A
dc.contributor.authorWestover, Kenneth D.
dc.contributor.authorHaigis, Kevin M.
dc.date.accessioned2020-07-01T20:19:08Z
dc.date.available2020-07-01T20:19:08Z
dc.date.issued2019-04
dc.date.submitted2019-03
dc.identifier.issn2159-8274
dc.identifier.issn2159-8290
dc.identifier.urihttps://hdl.handle.net/1721.1/126044
dc.description.abstractKRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor– induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer. SIGNIFICANCE: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties.en_US
dc.description.sponsorshipNational Institutes of Health (Grant U01CA215798)en_US
dc.language.isoen
dc.publisherAmerican Association for Cancer Research (AACR)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1158/2159-8290.cd-18-1220en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleTissue-Specific Oncogenic Activity of KRASA146Ten_US
dc.typeArticleen_US
dc.identifier.citationPoulin, Emily J. et al. "Tissue-Specific Oncogenic Activity of KRASA146T." Cancer Discovery 9, 6 (April 2019): 738-755 © 2019 American Association for Cancer Research Incen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Electrical Engineering and Computer Scienceen_US
dc.relation.journalCancer Discoveryen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2020-06-19T17:19:17Z
dspace.date.submission2020-06-19T17:19:20Z
mit.journal.volume9en_US
mit.journal.issue6en_US
mit.licenseOPEN_ACCESS_POLICY


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