A systems model of phosphorylation for inflammatory signaling events

• Published in: PloS one Vol. 9; no. 10; p. e110913
• Main Authors: Sadreev, Ildar I, Chen, Michael Z Q, Welsh, Gavin I, Umezawa, Yoshinori, Kotov, Nikolay V, Valeyev, Najl V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.10.2014; Public Library of Science (PLoS)
• Subjects: B cells; Biological response modifiers; Biology and Life Sciences; Biophysics; Cell Differentiation - genetics; Comparative analysis; Computer and Information Sciences; Cytokines; Cytokines - genetics; Cytokines - metabolism; Gene expression; Humans; Immune system; Inflammation; Inflammation - genetics; Inflammation - metabolism; Interferon; Interferon regulatory factor; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Kinases; Lymphocytes; Lymphocytes T; Mathematical models; Molecular modelling; Phenotypes; Phosphatase; Phosphorylation; Phosphorylation - genetics; Proteins; RNA polymerase; Signal Transduction - genetics; Signaling; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; T cells; T-Lymphocytes - metabolism; Transcription factors; United Kingdom > UK; Russia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110913

Phosphorylation is a fundamental biochemical reaction that modulates protein activity in cells. While a single phosphorylation event is relatively easy to understand, multisite phosphorylation requires systems approaches for deeper elucidation of the underlying molecular mechanisms. In this paper we develop a mechanistic model for single- and multi-site phosphorylation. The proposed model is compared with previously reported studies. We compare the predictions of our model with experiments published in the literature in the context of inflammatory signaling events in order to provide a mechanistic description of the multisite phosphorylation-mediated regulation of Signal Transducer and Activator of Transcription 3 (STAT3) and Interferon Regulatory Factor 5 (IRF-5) proteins. The presented model makes crucial predictions for transcription factor phosphorylation events in the immune system. The model proposes potential mechanisms for T cell phenotype switching and production of cytokines. This study also provides a generic framework for the better understanding of a large number of multisite phosphorylation-regulated biochemical circuits.