title: A systems model of phosphorylation for inflammatory signaling events.
abstract: 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.
authors.affiliation: Centre for Systems, Dynamics and Control, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Harrison Building, Exeter, United Kingdom.
authors.forename: Ildar I
authors.initials: II
authors.lastname: Sadreev
authors.affiliation: Department of Mechanical Engineering, The University of Hong Kong, Hong Kong, China.
authors.forename: Michael Z Q
authors.initials: MZ
authors.lastname: Chen
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, United Kingdom.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Department of Dermatology, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Umezawa
authors.affiliation: Biophysics and Bionics Lab, Institute of Physics, Kazan Federal University, Kazan, Russia.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Kotov
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, United Kingdom; Biophysics and Bionics Lab, Institute of Physics, Kazan Federal University, Kazan, Russia.
authors.forename: Najl V
authors.initials: NV
authors.lastname: Valeyev
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D016207:Cytokines; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D050796:STAT3 Transcription Factor