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dc.contributor.authorLi, Xinran
dc.contributor.authorLau, Amy Y T
dc.contributor.authorNg, Angel S N
dc.contributor.authorAldehaiman, Abdullah
dc.contributor.authorZhou, Yuan
dc.contributor.authorNg, Patrick K S
dc.contributor.authorArold, Stefan T.
dc.contributor.authorCheung, Lydia W T
dc.date.accessioned2021-09-13T08:41:59Z
dc.date.available2021-09-13T08:41:59Z
dc.date.issued2021-09-11
dc.identifier.citationLi, X., Lau, A. Y. T., Ng, A. S. N., Aldehaiman, A., Zhou, Y., Ng, P. K. S., … Cheung, L. W. T. (2021). Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases. Proceedings of the National Academy of Sciences, 118(37), e2101751118. doi:10.1073/pnas.2101751118
dc.identifier.issn0027-8424
dc.identifier.pmid34507989
dc.identifier.doi10.1073/pnas.2101751118
dc.identifier.urihttp://hdl.handle.net/10754/671188
dc.description.abstractThe phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.
dc.description.sponsorshipThis study was supported by the National Natural Science Foundation of China (Grants 81703066 and 82022078 to L.W.T.C.). S.T.A. and A.A. were supported by King Abdullah University of Science and Technology (KAUST) through the baseline fund and Awards FCC/1/1976-25 and REI/1/4446-01 from the Office of Sponsored Research. We thank I. Salem, R. Ramakrishnan, and S. Hong for their comments on the manuscript, as well as Huma Khurram and the KAUST Bioscience Core Lab for assistance with the mass spectrometry.
dc.relation.urlhttps://www.pnas.org/content/118/37/e2101751118/tab-article-info
dc.rightsThis open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleCancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.
dc.typeArticle
dc.contributor.departmentBioscience Program
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of America
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
dc.contributor.institutionInstitute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
dc.contributor.institutionCentre de Biologie Structurale, INSERM, Université de Montpellier, Montpellier 34090, France.
kaust.personAldehaiman, Abdullah
kaust.personArold, Stefan T.
kaust.grant.numberFCC/1/1976-25
kaust.grant.numberREI/1/4446-01
dc.date.accepted2021-07-02
refterms.dateFOA2021-09-13T08:43:54Z
kaust.acknowledged.supportUnitKAUST Bioscience Core Lab
kaust.acknowledged.supportUnitOffice of Sponsored Research


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This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
Except where otherwise noted, this item's license is described as This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).