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Title:Temperature dependence of the epidermal growth factor receptor signaling network can be accounted for by a kinetic model
Authors: G Moehren ; N Markevich ; O Demin ; A Kiyatkin ; Igor Goryanin ; JB Hoek ; BN Kholodenko
Date:Jan 2002
Publication Title:Biochemistry
Publication Type:Journal Article Publication Status:Published
Volume No:41(1) Page Nos:306-320
Stimulation of isolated hepatocytes with epidermal growth factor (EGF) causes rapid tyrosine phosphorylation of the EGF receptor (EGFR) and adapter/target proteins, which was monitored with 1 and 2 s resolution at 37, 20, and 4 degrees C. The temporal responses detected for multiple signaling proteins involve both transient and sustained phosphorylation patterns, which change dramatically at low temperatures. To account quantitatively for complex responses, we employed a mechanistic kinetic model of the EGFR pathway, formulated in molecular terms as cascades of protein interactions and phosphorylation and dephosphorylation reactions. Assuming differential temperature dependencies for different reaction groups, such as SH2 and PTB domain-mediated interactions, the EGFR kinase, and the phosphatases, good quantitative agreement was obtained between computer-simulated and measured responses. The kinetic model demonstrates that, for each protein-protein interaction, the dissociation rate constant, k(off), strongly decreases at low temperatures, whereas this decline may or may not be accompanied by a large decrease in the k(on) value. Temperature-induced changes in the maximal activities of the reactions catalyzed by the EGFR kinase were moderate, compared to such changes in the V(max) of the phosphatases. However, strong changes in both the V(max) and K(m) for phosphatases resulted in moderate changes in the V(max)/K(m) ratio, comparable to the corresponding changes in EGFR kinase activity, with a single exception for the receptor phosphatase at 4 degrees C. The model suggests a significant decrease in the rates of the EGF receptor dimerization and its dephosphorylation at 4 degrees C, which can be related to the phase transition in the membrane lipids. A combination of high-resolution experimental monitoring and molecular level kinetic modeling made it possible to quantitatively account for the temperature dependence of the integrative signaling responses.
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ACS Publications
Bibtex format
author = { G Moehren and N Markevich and O Demin and A Kiyatkin and Igor Goryanin and JB Hoek and BN Kholodenko },
title = {Temperature dependence of the epidermal growth factor receptor signaling network can be accounted for by a kinetic model},
journal = {Biochemistry},
publisher = {ACS},
year = 2002,
month = {Jan},
volume = {41(1)},
pages = {306-320},
doi = {10.1021/bi011506c},
url = {},

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