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| The EMBO Journal
(2000) 19, 5387–5395, doi:10.1093/emboj/19.20.5387 |
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| MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells |
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| Timothy P. Garrington, Tamotsu Ishizuka, Philip J. Papst, Kosuke Chayama, Saiphone Webb, Toshiaki Yujiri, Weiyong Sun, Sue Sather, David M. Russell, Spencer B. Gibson, Gordon Keller, Erwin W. Gelfand and Gary L. Johnson |
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Department of Pharmacology and University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue and Divisions of Cell Biology and Immunology, Departments of Pediatrics and Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA To whom correspondence should be addressed Gary L. Johnson, Gary.Johnson@uchsc.edu Received 5 June 2000; Revised 1 September 2000; Accepted 1 September 2000. |
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| Abstract |
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Ligation of the high-affinity IgE receptor (Fc 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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| Keywords: cytokine expression, ES-derived mast cells, MEKK2 knockouts |
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