title: MAP4K Family Kinases in Immunity and Inflammation.
abstract: MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been reported to induce JNK activation through activating the MAP3K-MAP2K cascade. The physiological roles of MAP4Ks in immunity and inflammation are largely unknown until recent studies using biochemical approaches and knockout mice. Surprisingly, JNK is not the major target of MAP4Ks in immune cells; MAP4Ks regulate immune responses through novel targets. HPK1 inhibits T-cell receptor (TCR) signaling and B-cell receptor signaling via inducing phosphorylation/ubiquitination of SLP-76 and BLNK, respectively. GLK activates TCR signaling through phosphorylating/activating PKCθ. T-cell-mediated immune responses and Th17-mediated experimental autoimmune diseases are enhanced in HPK1 knockout mice but ameliorated in GLK knockout mice. Consistently, HPK1 levels are decreased in peripheral blood mononuclear cells and T cells from patients with psoriatic arthritis and systemic lupus erythematosus (SLE), respectively. Moreover, GLK levels are increased in T cells from patients with SLE, rheumatoid arthritis, or adult-onset Still's disease; the percentages of GLK-overexpression T cells are correlated with the disease activity. In addition, HGK phosphorylates and induces TRAF2 protein degradation, leading to negative regulation of IL-6 production in resting T cells. Loss of HGK in T cells results in spontaneous systemic inflammation and type 2 diabetes in mice. HGK is also involved in cancer cell migration. To date, the phenotypes of knockout mice for GCK, KHS, and MINK have not been reported; the roles of these three MAP4Ks in immune cell signaling are discussed in this review. Taken together, MAP4K family kinases play diverse roles in immune cell signaling, immune responses, and inflammation.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan, ROC; Research and Development Center for Immunology, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Huai-Chia
authors.initials: HC
authors.lastname: Chuang
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan, ROC; Research and Development Center for Immunology, China Medical University, Taichung, Taiwan, ROC; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA. Electronic address: ttan@nhri.org.tw.
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion; D002465:Cell Movement; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000145:classification / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases
keywords: GCK; GLK; HGK; HPK1; Immunity; Inflammation; KHS; MAP4K; MINK