ArticleProceedings of the National Academy of Sciences of the United States of America2012
Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 195 papers, 1 of them a synthesis that pooled it.
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Who cites it
195 citing papers in PubMed, 1 synthesis or guideline pooled it, 312 citations in OpenAlex.
- Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.Clinical reviews in allergy & immunology · 2020Pooled it
- Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2016Trial
- Exceptional response to alpelisib in a heavily pretreated patient with metastatic breast cancer carrying a PIK3CA mutation outside SOLAR-1 eligible mutations: a case report.Acta oncologica (Stockholm, Sweden) · 2026Article
- Commentary beyond the ATP site: Cryo-EM views of allosteric PI3KActa pharmaceutica Sinica. B · 2026Article
- Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation.Molecular cell · 2026Article
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Seven complete comparative maps of allosteric mutations in a protein family.Nature communications · 2026Article
- A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant.The Journal of biological chemistry · 2026Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- Identification of pathological CD133+ endothelial cells in venous malformations.Frontiers in cardiovascular medicine · 2026Article
- Conventional and alternative approaches for targeting PIK3CA and PTEN alterations in head and neck, breast, and other cancers.Advances in biological regulation · 2026Review
- Understanding the distinct role of PI3K(p110Frontiers in cardiovascular medicine · 2026Review
- Understanding the conformational dynamics of PI3Kα due to helical domain mutations: insights from Markov state model analysis.Molecular diversity · 2025Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.bioRxiv : the preprint server for biology · 2025Article
- Structural and allosteric effects of the membrane-bound PI3Kα H1047R mutation and opportunities for drug discovery.Communications chemistry · 2025Article
- In Silico Discovery of a Novel Natural Product Targeting PI3Kα for the Treatment of Head and Neck Squamous Cell Carcinoma.International journal of molecular sciences · 2025Article
- Molecular substratification of endometrial carcinomas with no special molecular profile (NSMP) by using a limited NGS custom panel may facilitate effective patient selection for the PIK3CA-targeted therapy.Virchows Archiv : an international journal of pathology · 2025Article
- Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids.SLAS discovery : advancing life sciences R & D · 2025Article
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
135 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The p110α catalytic subunit (PIK3CA) is one of the most frequently mutated genes in cancer. We have examined the activation of the wild-type p110α/p85α and a spectrum of oncogenic mutants using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We find that for the wild-type enzyme, the natural transition from an inactive cytosolic conformation to an activated form on membranes entails four distinct events. Analysis of oncogenic mutations shows that all up-regulate the enzyme by enhancing one or more of these dynamic events. We provide the first insight into the activation mechanism by mutations in the linker between the adapter-binding domain (ABD) and the Ras-binding domain (RBD) (G106V and G118D). These mutations, which are common in endometrial cancers, enhance two of the natural activation events: movement of the ABD and ABD-RBD linker relative to the rest of the catalytic subunit and breaking the C2-iSH2 interface on binding membranes. C2 domain mutants (N345K and C420R) also mimic these events, even in the absence of membranes. A third event is breaking the nSH2-helical domain contact caused by phosphotyrosine-containing peptides binding to the enzyme, which is mimicked by a helical domain mutation (E545K). Interaction of the C lobe of the kinase domain with membranes is the fourth activation event, and is potentiated by kinase domain mutations (e.g., H1047R). All mutations increased lipid binding and basal activity, even mutants distant from the membrane surface. Our results elucidate a unifying mechanism in which diverse PIK3CA mutations stimulate lipid kinase activity by facilitating allosteric motions required for catalysis on membranes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.