Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

Xinran Li; Amy Y T Lau; Angel S N Ng; Abdullah Aldehaiman; Yuan Zhou; Patrick K S Ng; Stefan T. Arold; Lydia W T Cheung

doi:10.1073/pnas.2101751118

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

Xinran Li, Amy Y T Lau, Angel S N Ng, Abdullah Aldehaiman, Yuan Zhou, Patrick K S Ng, Stefan T. Arold, Lydia W T Cheung

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

The 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.

Original language	English (US)
Journal	Proceedings of the National Academy of Sciences of the United States of America
DOIs	https://doi.org/10.1073/pnas.2101751118
State	Published - Sep 11 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-09-14
Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01
Acknowledgements: This 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.

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General

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2101751118

https://repository.kaust.edu.sa/bitstream/10754/671188/1/e2101751118.full.pdf

Cite this

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title = "Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.",

abstract = "The 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.",

author = "Xinran Li and Lau, {Amy Y T} and Ng, {Angel S N} and Abdullah Aldehaiman and Yuan Zhou and Ng, {Patrick K S} and Arold, {Stefan T.} and Cheung, {Lydia W T}",

note = "KAUST Repository Item: Exported on 2021-09-14 Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01 Acknowledgements: This 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.",

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AU - Arold, Stefan T.

AU - Cheung, Lydia W T

N1 - KAUST Repository Item: Exported on 2021-09-14 Acknowledged KAUST grant number(s): FCC/1/1976-25, REI/1/4446-01 Acknowledgements: This 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.

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N2 - The 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.

AB - The 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.

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JF - Proceedings of the National Academy of Sciences of the United States of America

ER -

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases.

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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