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Characterization of rare oncogenic mutations in the kinase domain of Epidermal Growth Factor Receptor (EGFR)
Author(s) -
Ruan Zheng,
Katiyar Samiksha,
Kannan Natarajan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.665.4
Subject(s) - kinome , protein kinase domain , epidermal growth factor receptor , cancer research , kinase , protein kinase a , computational biology , biology , microbiology and biotechnology , mutant , cancer , genetics , gene
Epidermal growth factor receptor (EGFR) is activated by a variety of oncogenic mutations, many of which map to the intracellular protein kinase domain. While several recurrent mutations in the kinase domain are well characterized, mining of the Protein Kinase Ontology (ProKinO), which relates mutations to key functional motifs, reveals recurrent, but poorly characterized mutations in key functional regions. R776H and M766T are two such mutations in the alphaC‐beta4 and regulator spine of EGFR. We recently showed that the R776H functions as a “superacceptor” when paired with WT EGFR and exerts lateral phosphorylation activity (2). Molecular dynamics simulations identified a critical auto‐inhibitory interaction mediated by R776 that is relieved in the R776H mutant (2). M766T, on the other hand, activates EGFR by disrupting the inactive hydrophobic packing between the C‐helix and DFG motif, and stabilizing a water mediated hydrogen bond with the K745‐E762 salt bridge, formation of which is critical for kinase activation. Our experimental and computational studies provide new insights into kinase mutational activation and framework for identifying and characterizing rare drivers in the cancer kinome. Support or Funding Information Funding for N.K. from the American Cancer Society (RSG‐10‐ 188‐01‐TBE), Georgia Cancer Coalition (GCC) and University of Georgia is acknowledged. This study was supported in part by resources and technical expertise from the Georgia Advanced Computing Resource Center, a partnership between the University of Georgia's Office of the Vice President for Research and Office of the Vice President for Information Technology.