Biophysical Society Conference | Tahoe 2023

Proton Reactions: From Basic Science to Biomedical Applications

Tuesday Speaker Abstracts

CHARGE-INDUCED BIAS IN EGFR SIGNAL TRANSDUCTION ACROSS THE PLASMA MEMBRANE Kalina Hristova ; Daniel Wirth 1 ; Ece Ozdemir 1 ; 1 Johns Hopkins University, Materials Science, Baltimore, MD, USA The 58 receptor tyrosine kinases (RTKs) are critically important for human development, and are implicated in many growth disorders and cancers. RTK mutations to charged amino acids often cause disease, but the consequences of the introduced charges for RTK signal transduction across the plasma membrane are unexplored. We introduce a methodology to identify and quantify bias in RTK signaling across the plasma membrane without contributions from feedback loops and system bias. We show that RTK biased signaling can occur in the first step of signal transduction in response to different ligands and as a consequence of a pathogenic mutation introducing an arginine. Ligand bias and mutation-induced bias are uncoupled based on a comprehensive data set of dose response curves acquired for three ligands, EGF, TGF α and epiregulin, for wild-type EGFR and for the oncogenic L834R EGFR mutant found in patients with non-small-cell lung cancer. The demonstration of charge-induced bias in RTK signal transduction across the plasma membrane will open new avenues for the exploration of RTK biased inhibitors as highly specific anti-cancer therapies.

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