Aggregation of the FcepsilonRI on mast cells stimulates c-Jun amino-terminal kinase activity. A response inhibited by wortmannin.
Aggregation of the high-affinity Fc receptors for immunoglobulin E (IgE) (FcepsilonRI) on the surface of mast cells initiates intracellular signal transduction pathways including the tyrosine phosphorylation of cellular proteins, phosphoinositide hydrolysis, an increase in intracellular calcium, and protein kinase C activation. These signals are believed to be involved in the exocytic release of inflammatory mediators such as vasoactive amines, cytokines, and lipid metabolites. However, the downstream consequences of these early activation events are not well defined. One exception is the activation of the extracellular signal-regulated kinases/mitogen-activated protein kinases. One member of the mitogen-activated protein kinase superfamily, designated c-Jun amino-terminal kinase (JNK), has been recently identified. JNK is activated following dual phosphorylation at a Thr-Pro-Tyr motif in response to diverse stimuli including tumor necrosis factor-alpha, heat shock, or ultraviolet irradiation. We found that JNK was strongly activated by antigen cross-linking in a mouse mast cell line passively sensitized with ovalbumin-specific IgE. Anti-mouse IgE antibody also activated JNK. MEK kinase 1 (MEKK1) which activates the JNK activator, JNK kinase (JNKK), was similarly activated by antigen stimulation. JNK but not p42(erk2) activation induced by antigen was significantly inhibited in the presence of wortmannin, a known inhibitor of phosphatidylinositol 3-kinase. These results indicate that in response to the aggregation of FcepsilonRI on mast cells, phosphatidylinositol 3-kinase activation is involved in the stimulation of the MEKK1, JNKK, JNK pathway.
Ishizuka
T
T
Division of Basic Sciences, Department of Pediatrics, and the Program in Molecular Signal Transduction, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Oshiba
A
A
Sakata
N
N
Terada
N
N
Johnson
G L
GL
Gelfand
E W
EW
D000595:Amino Acid Sequence; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D000941:Antigens; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D017455:Receptors, IgE; D007073:Immunoglobulin E; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D000077191:Wortmannin