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MEK Kinase 1: Kinase Domain Deficiency in Mice Reveals a Role in Orchestrating the Thymus-Dependent Immunity and TNFR Family Signaling

  • Ewen Gallagher
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)

Abstract

Almost 20 years ago early work led to the cloning and identification of mitogen-activated protein kinases (MAPKs) as the apical component of a biochemical phospho-relay circuit that is activated by upstream MAPK kinases (MAP2Ks) and MAP2K kinases (MAP3Ks). The c-Jun N-terminal kinase (JNK) and p38 sub-families of MAPKs were identified as being activated following ligation of the cytokine tumor necrosis factor (TNF)-α to its principal receptor TNF receptor (TNFR) 1, leading to receptor trimerization and the initiation of downstream signaling. Part of the initial struggle to understand the role of MAPKs by biochemical overexpression studies has now been overcome through the generation of mutant mice that harbor genetic alterations in components of the JNK and p38 pathways. MEK kinase 1 (MEKK1) was initially identified as a kinase that could activate several MAPK pathways upon overexpression in cell lines and was found to become activated following TNF-α treatment of cells. The later generation of the Mekk1 kinase-deficient mouse model (Mekk1 ΔKD ) demonstrated that this MAP3K plays a key role in thymus-dependent (TD) immune responses and B and T-cell signaling. In particular, careful examination of the pathologies presented by the Mekk1 ΔKD model identified severe deficits in germinal center formation in the secondary lymphoid follicles, TD antibody production, and lymphocyte proliferation. Reconstitution of the μMT B-cell-deficient host strain with Mekk1 ΔKD or WT bone marrow led to the identification of an intrinsic defect in Mekk1 ΔKD B cells and the subsequent careful examination of Mekk1 B-cell signaling then revealed severe JNK- and p38-activation deficits in TNFR family member signaling, notably for CD40 and B-cell activating factor (BAFF) receptors.

Keywords

MAPK Signaling Germinal Center Formation HECT Domain TNFR Family Null Embryonic Stem 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of ImmunologyImperial College, 10th Floor, Commonwealth Building, Hammersmith HospitalLondonUK

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