期刊
EMBO JOURNAL
卷 19, 期 20, 页码 5387-5395出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/19.20.5387
关键词
cytokine expression; ES-derived mast cells; MEKK2 knockouts
资金
- NCI NIH HHS [CA85276, K08 CA085276] Funding Source: Medline
- NIDDK NIH HHS [R01 DK037871, DK37871] Funding Source: Medline
- NIGMS NIH HHS [R01 GM030324, GM30324, R37 GM030324] Funding Source: Medline
Ligation of the high-affinity IgE receptor (Fc epsilon RI) 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.
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