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      The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells

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          Abstract

          The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed.

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          The JAK-STAT signaling pathway: input and output integration.

          Peter Murray (2007)
          Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.
          Article 0 comments Cited 365 times – based on 0 reviews     Review now
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            IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.

            Matthew A Burchill, Jianying Yang, Christine Vogtenhuber … (2007)
            IL-2(-/-) mice develop autoimmunity despite having relatively normal numbers of regulatory T cells (Tregs). In contrast, we demonstrate that IL-2(-/-) x IL-15(-/-) and IL-2Rbeta(-/-) mice have a significant decrease in Treg numbers. Ectopic expression of foxp3 in a subset of CD4(+) T cells rescued Treg development and prevented autoimmunity in IL-2Rbeta(-/-) mice, suggesting that IL-2Rbeta-dependent signals regulate foxp3 expression in Tregs. Subsequent analysis of IL-2Rbeta-dependent signal transduction pathways established that the transcription factor STAT5 is necessary and sufficient for Treg development. Specifically, T cell-specific deletion of STAT5 prevented Treg development; conversely, reconstitution of IL-2Rbeta(-/-) mice with bone marrow cells expressing an IL-2Rbeta mutant that exclusively activates STAT5 restored Treg development. Finally, STAT5 binds to the promoter of the foxp3 gene suggesting that IL-2Rbeta-dependent STAT5 activation promotes Treg differentiation by regulating expression of foxp3.
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              Signaling through scaffold, anchoring, and adaptor proteins.

              T. Pawson, J D Scott (1997)
              The process by which extracellular signals are relayed from the plasma membrane to specific intracellular sites is an essential facet of cellular regulation. Many signaling pathways do so by altering the phosphorylation state of tyrosine, serine, or threonine residues of target proteins. Recently, it has become apparent that regulatory mechanisms exist to influence where and when protein kinases and phosphatases are activated in the cell. The role of scaffold, anchoring, and adaptor proteins that contribute to the specificity of signal transduction events by recruiting active enzymes into signaling networks or by placing enzymes close to their substrates is discussed.
              Article 0 comments Cited 162 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Farhad Seif: Farhad.Seif@outlook.com
                Majid Khoshmirsafa: Mj.khoshmirsafa@hotmail.com
                Hossein Aazami: Hossein.aazami@gmail.com
                Monireh Mohsenzadegan: m-mohsenzadegan@razi.tums.ac.ir
                Gholamreza Sedighi: Sedigh_1352@yahoo.com
                Mohammadali Bahar: 009888622652 , Mobahar@yahoo.com
                Journal
                Journal ID (nlm-ta): Cell Commun Signal
                Journal ID (iso-abbrev): Cell Commun. Signal
                Title: Cell Communication and Signaling : CCS
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1478-811X
                Publication date (Electronic): 21 June 2017
                Publication date PMC-release: 21 June 2017
                Publication date Collection: 2017
                Volume: 15
                Electronic Location Identifier: 23
                Affiliations
                [1 ]GRID grid.411746.1, ENT and Head and Neck Research Center and Department, Hazrat Rasoul Akram Hospital, , Iran University of Medical Sciences, ; Tehran, Iran
                [2 ]GRID grid.411746.1, Department of immunology, school of medicine, , Iran University of Medical Sciences, ; Tehran, Iran
                [3 ]GRID grid.411746.1, Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, , Iran University of Medical Sciences, ; Tehran, Iran
                Article
                Publisher ID: 177
                DOI: 10.1186/s12964-017-0177-y
                PMC ID: 5480189
                PubMed ID: 28637459
                SO-VID: cf6df04e-989f-4d4e-b889-de8fcad5c436
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 20 April 2017
                Date accepted : 2 June 2017
                Categories
                Subject: Review
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                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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