GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38
Open Access
- 17 March 2009
- journal article
- retracted article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (11), 4372-4377
- https://doi.org/10.1073/pnas.0812642106
Abstract
Systemic inflammation arising from the organismal distribution of pathogen-associated molecular patterns is a major cause of clinical morbidity and mortality. Herein we report a critical and previously unrecognized in vivo role for germinal center kinase (GCK, genome nomenclature: map4k2), a mammalian Sterile 20 (STE20) orthologue, in PAMP signaling, and systemic inflammation. We find that disruption of gck in mice strongly impairs PAMP-stimulated macrophage cytokine and chemokine release and renders mice resistant to endotoxin-mediated lethality. Bone marrow transplantation studies show that hematopoietic cell GCK signaling is essential to systemic inflammation. Disruption of gck substantially reduces PAMP activation of macrophage Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) via reduced activation of the MAPK-kinase-kinases (MAP3Ks) mixed lineage kinases (MLKs)-2 and -3. Extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB) activation are largely unaffected. Thus, GCK is an essential PAMP effector coupling JNK and p38, but not ERK or NF-κB to systemic inflammation.Keywords
This publication has 51 references indexed in Scilit:
- Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling ComplexScience, 2008
- TAK1 is required for the survival of hematopoietic cells and hepatocytes in miceThe Journal of Experimental Medicine, 2008
- Recognition of microorganisms and activation of the immune responseNature, 2007
- MEKK3 is essential for lipopolysaccharide‐induced interleukin‐6 and granulocyte–macrophage colony‐stimulating factor production in macrophagesImmunology, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006
- Germinal Center Kinase Is Required for Optimal Jun N-Terminal Kinase Activation by Toll-Like Receptor Agonists and Is Regulated by the Ubiquitin Proteasome System and Agonist-Induced, TRAF6-Dependent StabilizationMolecular and Cellular Biology, 2004
- Toll-like receptor control of the adaptive immune responsesNature Immunology, 2004
- The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisationCellular Signalling, 2004
- Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3Nature Immunology, 2003
- Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling PathwayScience, 2003