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      T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion


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          MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck Cre/+ Map3k1 f/f mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. Lck Cre/+ Map3k1 f/f mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27 Kip1 (encoded by Cdkn1b).

          Graphical Abstract


          • iNKT cell expansion is aberrant in Lck Cre/+ Map3k1 f/f mice

          • Lck Cre/+ Map3k1 f/f mice have enhanced liver damage in response to glycolipids

          • Mekk1 regulates TCR-dependent Jnk activation

          • Mekk1 regulates p27 Kip1 expression to regulate proliferation


          Suddason et al. use a T-cell-specific deletion of Map3k1 to show that Mekk1 regulates TCR-dependent Jnk activation and Cdkn1b expression to drive proliferation in response to antigen.

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          Most cited references 39

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          Missing pieces in the NF-kappaB puzzle.

          The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
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            CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.

             J Cui,  H Koseki,  I Toura (1997)
            Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the Valpha14 and Jalpha281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C26) and sphingosine base (C18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.
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              MAP kinases in the immune response.

              MAP kinases are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes. In mammalian species, MAP kinases are involved in all aspects of immune responses, from the initiation phase of innate immunity, to activation of adaptive immunity, and to cell death when immune function is complete. In this review, we summarize recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses.

                Author and article information

                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                07 January 2016
                26 January 2016
                07 January 2016
                : 14
                : 3
                : 449-457
                [1 ]Department of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK
                Author notes
                []Corresponding author teshas7@ 123456yahoo.com
                [∗∗ ]Corresponding author ewengallagher@ 123456outlook.com
                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


                Cell biology


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