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A Computational Study of Feedback Effects on Signal Dynamics in a Mitogen‐Activated Protein Kinase (MAPK) Pathway Model
Author(s) -
Asthagiri Anand R.,
Lauffenburger Douglas A.
Publication year - 2001
Publication title -
biotechnology progress
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 129
eISSN - 1520-6033
pISSN - 8756-7938
DOI - 10.1021/bp010009k
Subject(s) - negative feedback , mapk/erk pathway , upstream and downstream (dna) , signal transduction , chinese hamster ovary cell , microbiology and biotechnology , kinase , biology , upstream (networking) , receptor , computer science , physics , biochemistry , computer network , quantum mechanics , voltage
Abstract Exploiting signaling pathways for the purpose of controlling cell function entails identifying and manipulating the information content of intracellular signals. As in the case of the ubiquitously expressed, eukaryotic mitogen‐activated protein kinase (MAPK) signaling pathway, this information content partly resides in the signals' dynamical properties. Here, we utilize a mathematical model to examine mechanisms that govern MAPK pathway dynamics, particularly the role of putative negative feedback mechanisms in generating complete signal adaptation, a term referring to the reset of a signal to prestimulation levels. In addition to yielding adaptation of its direct target, feedback mechanisms implemented in our model also indirectly assist in the adaptation of signaling components downstream of the target under certain conditions. In fact, model predictions identify conditions yielding ultra‐desensitization of signals in which complete adaptation of target and downstream signals culminates even while stimulus recognition (i.e., receptor‐ligand binding) continues to increase. Moreover, the rate at which signal decays can follow first‐order kinetics with respect to signal intensity, so that signal adaptation is achieved in the same amount of time regardless of signal intensity or ligand dose. All of these features are consistent with experimental findings recently obtained for the Chinese hamster ovary (CHO) cell lines (Asthagiri et al., J. Biol. Chem. 1999 , 274 , 27119−27127). Our model further predicts that although downstream effects are independent of whether an enzyme or adaptor protein is targeted by negative feedback, adaptor‐targeted feedback can “back‐propagate” effects upstream of the target, specifically resulting in increased steady‐state upstream signal. Consequently, where these upstream components serve as nodes within a signaling network, feedback can transfer signaling through these nodes into alternate pathways, thereby promoting the sort of signaling cross‐talk that is becoming more widely appreciated.