title: Dynamic Redox Regulation of IL-4 Signaling.
abstract: Quantifying the magnitude and dynamics of protein oxidation during cell signaling is technically challenging. Computational modeling provides tractable, quantitative methods to test hypotheses of redox mechanisms that may be simultaneously operative during signal transduction. The interleukin-4 (IL-4) pathway, which has previously been reported to induce reactive oxygen species and oxidation of PTP1B, may be controlled by several other putative mechanisms of redox regulation; widespread proteomic thiol oxidation observed via 2D redox differential gel electrophoresis upon IL-4 treatment suggests more than one redox-sensitive protein implicated in this pathway. Through computational modeling and a model selection strategy that relied on characteristic STAT6 phosphorylation dynamics of IL-4 signaling, we identified reversible protein tyrosine phosphatase (PTP) oxidation as the primary redox regulatory mechanism in the pathway. A systems-level model of IL-4 signaling was developed that integrates synchronous pan-PTP oxidation with ROS-independent mechanisms. The model quantitatively predicts the dynamics of IL-4 signaling over a broad range of new redox conditions, offers novel hypotheses about regulation of JAK/STAT signaling, and provides a framework for interrogating putative mechanisms involving receptor-initiated oxidation.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Dwivedi
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Gran
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.
authors.forename: Pritha
authors.initials: P
authors.lastname: Bagchi
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States of America.|Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Kemp
mesh_terms: D000465:Algorithms; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D019169:Jurkat Cells; D008954:Models, Biological; D010084:Oxidation-Reduction; D017027:Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*
chemical_list: C508598:IL4 protein, human; D015847:Interleukin-4; D017027:Protein Tyrosine Phosphatases