MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells.
Ligation of the high-affinity IgE receptor (FcepsilonRI) or of c-Kit stimulates cytokine production in mast cells. We show that MEK kinase 2 (MEKK2), a MAPK kinase kinase (MAP3K) that regulates the JNK and ERK5 pathways, is required for cytokine production in embryonic stem (ES) cell-derived mast cells (ESMC). Targeted disruption of the MEKK2 or MEKK1 gene was used to abolish expression of the respective kinases in ESMC. Transcription of specific cytokines in response to IgE or c-Kit ligand was markedly reduced in MEKK2(-/-) ESMC relative to wild-type ESMC. Cytokine production in MEKK1(-/-) ESMC was similar to that of wild-type ESMC, demonstrating the specificity of MEKK2 in signaling cytokine gene regulation. MEKK2(-/-) ESMC also lost receptor-mediated stimulation of JNK. In contrast, JNK activation in response to UV irradiation was normal, showing that MEKK2 is required for receptor signaling but not for cellular stress responses. MEKK2 is the first MAP3K shown to be required for mast cell tyrosine kinase receptor signaling controlling cytokine gene expression.
Garrington
T P
TP
Department of Pharmacology and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80206, USA.
Ishizuka
T
T
Papst
P J
PJ
Chayama
K
K
Webb
S
S
Yujiri
T
T
Sun
W
W
Sather
S
S
Russell
D M
DM
Gibson
S B
SB
Keller
G
G
Gelfand
E W
EW
Johnson
G L
GL
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011940:Receptor Aggregation; D017455:Receptors, IgE / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D012333:RNA, Messenger; D017455:Receptors, IgE; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482578:Map3k1 protein, mouse; C482619:Map3k2 protein, mouse