ArticleBiochemistry2015
Mechanistic Insights into R776H Mediated Activation of Epidermal Growth Factor Receptor Kinase.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- A molecular dynamics protocol for rapid prediction of EGFR overactivation and its application to the rare mutations S768I, S768N, D761N.Computational and structural biotechnology journal · 2025Article
- Survivin Mediates Mitotic Onset in HeLa Cells Through Activation of the Cdk1-Cdc25B Axis.Research square · 2024Article
- Case report: identification of EGFR R776H and FANCE R381H germline mutations in a patient with multiple pulmonary nodules.Journal of cancer research and clinical oncology · 2023Article
- A Primary Lung and Breast Cancer Patient with GermlineOncoTargets and therapy · 2023Article
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- Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.Frontiers in immunology · 2022Article
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- Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease.IUBMB life · 2020Review
- Absence of EGFR C797S Mutation in Tyrosine Kinase Inhibitor-Naïve Non-Small Cell Lung Cancer Tissues.Pathology oncology research : POR · 2020Article
- Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring ActivatingClinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- EGFRJournal of oncology · 2019Review
- Altered conformational landscape and dimerization dependency underpins the activation of EGFR byProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.Scientific reports · 2018Article
- Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation.Chemical reviews · 2018Review
- Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins.Science signaling · 2017Article
- Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The "Rotation Model".Cells · 2017Review
- Rational design of non-resistant targeted cancer therapies.Scientific reports · 2017Article
- Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase.Biochemistry · 2017Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The epidermal growth factor receptor (EGFR) kinase is activated by a variety of mutations in human cancers. R776H is one such recurrent mutation (R752H in another numbering system) in the αC-β4 loop of the tyrosine kinase domain that activates EGFR in the absence of the activating EGF ligand. However, the mechanistic details of how R776H contributes to kinase activation are not well understood. Here using cell-based cotransfection assays, we show that the R776H mutation activates EGFR in a dimerization-dependent manner by preferentially adopting the acceptor position in the asymmetric dimer. The acceptor function, but not the donor function, is enhanced for the R776H mutant, supporting the "superacceptor" hypothesis proposed for oncogenic mutations in EGFR. We also find that phosphorylation of monomeric EGFR is increased by R776H mutation, providing insights into EGFR lateral phosphorylation and oligomerization. On the basis of molecular modeling and molecular dynamics simulation, we propose a model in which loss of key autoinhibitory αC-helix capping interaction and alteration of coconserved cis regulatory interactions between the kinase domain and the flanking regulatory segments contribute to mutational activation. Since the R776 equivalent position is mutated in ErbB2 and ErbB4, our studies have implications for understanding kinase mutational activation in other ErbB family members as well.
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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.