ArticleThe FEBS journal2015
Oncogenic mutations weaken the interactions that stabilize the p110α-p85α heterodimer in phosphatidylinositol 3-kinase α.
Article in The FEBS journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Clinical Significance of PIK3CA Gene in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.BioMed research international · 2020Pooled it
- Unveiling the wound-healing potential of Pisum sativum aerial biomass through integrated bioassay-guided, LC-MS/MS, and network pharmacology approaches.BMC complementary medicine and therapies · 2026Article
- 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
- The Effect and Treatment of PIK3CA Mutations in Breast Cancer: Current Understanding and Future Directions.Medicina (Kaunas, Lithuania) · 2025Review
- Decoding the functional impact of the cancer genome through protein-protein interactions.Nature reviews. Cancer · 2025Review
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- Survey for Activating Oncogenic Mutation Variants in Metazoan Germline Genes.Journal of molecular evolution · 2024Article
- A deep learning-based theoretical protocol to identify potentially isoform-selective PI3Kα inhibitors.Molecular diversity · 2024Article
- Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms.Blood advances · 2023Article
- Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα).Biochimica et biophysica acta. Reviews on cancer · 2023Review
- Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy.Cancer discovery · 2022Article
- Class I PI3K Biology.Current topics in microbiology and immunology · 2022Article
- The orchestrated signaling by PI3Kα and PTEN at the membrane interface.Computational and structural biotechnology journal · 2022Review
- Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.The Journal of clinical investigation · 2021Article
- Allicin protects against myocardial I/R by accelerating angiogenesis via the miR-19a-3p/PI3K/AKT axis.Aging · 2021Article
- Allosteric Activation of PI3Kα Results in Dynamic Access to Catalytically Competent Conformations.Structure (London, England : 1993) · 2020Article
- mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs).Frontiers in endocrinology · 2020Review
- Structural Perturbations due to Mutation (H1047R) in Phosphoinositide-3-kinase (PI3Kα) and Its Involvement in Oncogenesis: An in Silico Insight.ACS omega · 2019Article
- The mechanism of PI3Kα activation at the atomic level.Chemical science · 2019Article
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4 authors at 3 institutions in 1 country.
Funding
Abstract
Phosphatidylinositol 3-kinase (PI3K) α is a heterodimeric lipid kinase that catalyzes the conversion of phosphoinositol-4,5-bisphosphate to phosphoinositol-3,4,5-trisphosphate. The PI3Kα signaling pathway plays an important role in cell growth, proliferation, and survival. This pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110α PI3Kα subunit, is mutated. Its mutation often results in gain of enzymatic activity; however, the mechanism of activation by oncogenic mutations remains unknown. Here, using computational methods, we show that oncogenic mutations that are far from the catalytic site and increase the enzymatic affinity destabilize the p110α-p85α dimer. By affecting the dynamics of the protein, these mutations favor the conformations that reduce the autoinhibitory effect of the p85α nSH2 domain. For example, we determined that, in all of the mutants, the nSH2 domain shows increased positional heterogeneity as compared with the wild-type, as demonstrated by changes in the fluctuation profiles computed by normal mode analysis of coarse-grained elastic network models. Analysis of the interdomain interactions of the wild-type and mutants at the p110α-p85α interface obtained with molecular dynamics simulations suggest that all of the tumor-associated mutations effectively weaken the interactions between p110α and p85α by disrupting key stabilizing interactions. These findings have important implications for understanding how oncogenic mutations change the conformational multiplicity of PI3Kα and lead to increased enzymatic activity. This mechanism may apply to other enzymes and/or macromolecular complexes that play a key role in cell signaling.
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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.