The MAPK scaffold kinase suppressor of Ras is involved in ERK activation by stress and proinflammatory cytokines and induction of arthritis.
The MAPK ERK is required for LPS-induced TNF production by macrophages. Although the scaffold kinase suppressor of Ras (KSR)1 is required for efficient Erk activation by mitogenic stimuli, the role of KSR1 in ERK activation by inflammatory and stress stimuli is unknown. In this study, we examined the effects of KSR deficiency on ERK activation by stress stimuli and show that ERK activation by TNF, IL-1, and sorbitol is attenuated in the absence of KSR1. To determine the significance of this defect in vivo, we tested KSR-deficient mice using a passive transfer model of arthritis. We found that the induction of arthritis is impaired in the absence of KSR. Thus, KSR plays a role in ERK activation during inflammatory and stress responses both in vitro and in vivo.
Fusello
Angela M
AM
Department of Pathology and Department of Immunology, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110, USA.
Mandik-Nayak
Laura
L
Shih
Fei
F
Lewis
Robert E
RE
Allen
Paul M
PM
Shaw
Andrey S
AS
D000818:Animals; D001168:Arthritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009997:Osmotic Pressure; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013012:Sorbitol / Q000494:pharmacology; D013489:Suppression, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics
D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D013012:Sorbitol; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1; D018631:ras Proteins