An interaction library for the FcεRI signaling network

HYPOTHESIS & THEORY ARTICLE

Front. Immunol., 15 April 2014 | doi: 10.3389/fimmu.2014.00172

Lily A. Chylek^1,2, David A. Holowka¹, Barbara A. Baird¹* and

 William S. Hlavacek²*

• 1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA
• 2Los Alamos National Laboratory, Theoretical Division, Center for Non-linear Studies, Los Alamos, NM, USA

Antigen receptors play a central role in adaptive immune responses. Although the molecular networks associated with these receptors have been extensively studied, we currently lack a systems-level understanding of how combinations of non-covalent interactions and post-translational modifications are regulated during signaling to impact cellular decision-making. To fill this knowledge gap, it will be necessary to formalize and piece together information about individual molecular mechanisms to form large-scale computational models of signaling networks. To this end, we have developed an interaction library for signaling by the high-affinity IgE receptor, FcεRI. The library consists of executable rules for protein–protein and protein–lipid interactions. This library extends earlier models for FcεRI signaling and introduces new interactions that have not previously been considered in a model. Thus, this interaction library is a toolkit with which existing models can be expanded and from which new models can be built. As an example, we present models of branching pathways from the adaptor protein Lat, which influence production of the phospholipid PIP3 at the plasma membrane and the soluble second messenger IP3. We find that inclusion of a positive feedback loop gives rise to a bistable switch, which may ensure robust responses to stimulation above a threshold level. In addition, the library is visualized to facilitate understanding of network circuitry and identification of network motifs.

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Keywords: immunoreceptor signaling, IgE receptors (FcεRI), mast cells, knowledge engineering, computational modeling, network motifs, feed-forward loops, visualization

Citation: Chylek LA, Holowka DA, Baird BA and Hlavacek WS (2014) An interaction library for the FcεRI signaling network.Front. Immunol. 5:172. doi: 10.3389/fimmu.2014.00172

Received: 11 December 2013; Accepted: 31 March 2014;
Published online: 15 April 2014.

Edited by:

Rob J. De Boer, Utrecht University, Netherlands

Reviewed by:

Christopher E. Rudd, University of Cambridge, UK
Grégoire Altan-Bonnet, Memorial Sloan-Kettering Cancer Center, USA

Copyright: © 2014 Chylek, Holowka, Baird and Hlavacek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Barbara A. Baird, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA e-mail: bab13@cornell.edu;
William S. Hlavacek, Los Alamos National Laboratory, Theoretical Division, Center for Nonlinear Studies, Los Alamos, NM 87545, USA e-mail: wish@lanl.gov