Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Activation Mechanism of R776H mutation in Epidermal Growth Factor Receptor (EGFR)
Activating mutations in EGFR have been implicated in a variety of human cancers (Robert Roskoski Jr., 2014). R776H is one such recurrent mutation in the hinge region of the kinase domain and is known to activate EGFR in a ligand independent manner (Jan van Noesel et al., 2013, Daniel Ian McSkimming et al., 2015). However, the atomic details of how R776H contributes to kinase activation are not well understood. Here, using a combination of cell-based kinase assays and molecular dynamics simulations, we investigate the activation mechanism of R776H mutant. Our studies reveal that R776H mediated activation of EGFR depends on the asymmetric dimer in that mutant EGFR is active only in the dimeric form, but not in the monomeric form. The asymmetric dimer complex functions as a holoenzyme to phosphorylate monomeric EGFR, highlighting an important lateral phosphorylation pathway of EGFR oligomers. Molecular dynamics simulations indicate that the R776H mutation relieves auto-inhibitory interactions with the C-helix and C-terminal tail. In particular, a conserved helix capping interaction between R776 and A767 is lost in the mutant form, resulting in C-helix disorder. Stabilization of the C-helix and loss of auto-inhibitory interactions with the C-terminal tail promote kinase activation and downstream signaling. Because R776 is a mutational hotspot in the kinome, our studies have implications for understanding mutational activation/regulation of kinases in other diseases, and for the design of mutant-specific kinase inhibitors.
This research has been supported by American Cancer Society (RSG-10-188-01-TBE) and Georgia Cancer Coalition (GCC).
Jan van Noesel, Ward H. van der Ven, Theo A.M. van Os, Peter W.A. Kunst, J. W. and R. J. A. R. (2013) Activating Germline R776H Mutation in the Epidermal Growth Factor Receptor Associated With Lung Cancer With Squamous Differentiation. J. Clin. Oncol. 31, 161-164
Daniel Ian McSkimming, Shima Dastgheib, Eric Talevich, Anish Narayanan, Samiksha Katiyar, Susan S. Taylor, Krys Kochut and Natarajan Kannan, ProKinO: A Unified Resource for Mining the Cancer Kinome (2015), Hum Mutat. 36, 175-186
Institute of Bioinformatics