Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases
| Autor: | Lydia W.T. Cheung, Angel S N Ng, Abdullah Aldehaiman, Amy Y T Lau, Patrick Kwok Shing Ng, Stefan T. Arold, Yuan Zhou, Xinran Li |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Receptor
ErbB-3 Class I Phosphatidylinositol 3-Kinases Allosteric regulation P110α SH2 domain medicine.disease_cause Receptor tyrosine kinase src Homology Domains Transactivation Phosphatidylinositol 3-Kinases Protein Domains Catalytic Domain Cell Line Tumor Neoplasms medicine Humans skin and connective tissue diseases Protein kinase B PI3K/AKT/mTOR pathway Mutation Multidisciplinary biology receptor tyrosine kinases Chemistry Receptor Protein-Tyrosine Kinases p85α Cell Biology Biological Sciences HCT116 Cells Class Ia Phosphatidylinositol 3-Kinase biology.protein Cancer research Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Phosphoinositide 3-kinase activation typically occurs following stimulation by upstream receptor tyrosine kinases (RTKs), which alleviate p110α inhibition by p85α. p85α and p110α driver mutations have been reported to activate p110α by disrupting the inhibitory interface between p85α and p110α. This study revealed that driver mutations in the p85α N-terminal SH2 domain can enhance p110α activity by inducing the activation of multiple RTKs. Furthermore, combination treatment with RTK and AKT inhibitors provides synergistic therapeutic efficacy. This previously uncharacterized oncogenic mechanism presents the exploitable vulnerability of a class of p85α mutant tumors. 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. |
| Databáze: | OpenAIRE |
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