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Influence of kinetics of drug binding on EGFR signaling: A comparative study of three EGFR signaling pathway models
Author(s) -
Bairy Sneha,
Wong Chung F.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23072
Subject(s) - signal transduction , kinase , epidermal growth factor receptor , mapk/erk pathway , microbiology and biotechnology , protein kinase a , chemistry , epidermal growth factor , extracellular , biology , biochemistry , receptor
We used three models of the epidermal growth factor receptor (EGFR) signaling pathway mimicking three different cell lines to study the effects of kinetics of drug binding on influencing molecular signaling in the pathways. With no incubation of drugs before the external cue epidermal growth factor (EGF) was applied, we found that fast kinetics of binding to protein kinases was advantageous in suppressing the production of the Extracellular signal‐regulated kinase (ERK) that triggers cell proliferation, with some exceptions. Incubation of a drug with a protein kinase target for an hour before a pathway was initiated with an external cue made kinetics less significant, so did high concentration of drugs. In addition, we found that applying a drug to a protein kinase mostly affected downstream signaling although upstream events were also affected in a few cases. In examining whether applying two drugs to two protein kinase targets in the pathways could produce synergistic effects, we found positive, negative, or no effects, depending on the protein kinases targeted and the pathway model considered. Proteins 2011; © 2011 Wiley‐Liss, Inc.