GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38.
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-kappaB (NF-kappaB) activation are largely unaffected. Thus, GCK is an essential PAMP effector coupling JNK and p38, but not ERK or NF-kappaB to systemic inflammation.
Zhong
Jian
J
The Molecular Cardiology Research Institute, and Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA.
Gavrilescu
L Cristina
LC
Molnár
Arpád
A
Murray
Lauren
L
Garafalo
Stephen
S
Kehrl
John H
JH
Simon
Amy R
AR
Van Etten
Richard A
RA
Kyriakis
John M
JM
D053607:Adrenomedullin / Q000494:pharmacology; D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D000081410:Germinal Center Kinases; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007249:Inflammation / Q000209:etiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D000081410:Germinal Center Kinases; D016328:NF-kappa B; D051192:Receptors, Pattern Recognition; D053607:Adrenomedullin; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases