Disruption of Mekk2 in mice reveals an unexpected role for MEKK2 in modulating T-cell receptor signal transduction.
MEKK2 is a member of the mitogen-activated protein kinase (MAPK) kinase kinase gene family involved in regulating multiple MAPK signaling pathways. To elucidate the in vivo function of MEKK2, we generated mice carrying a targeted mutation in the Mekk2 locus. Mekk2(-/-) mice are viable and fertile. Major subsets of thymic and spleen T cells in Mekk2-deficient mice were indistinguishable from those in wild-type mice. B-cell development appeared to proceed similarly in the bone marrow of Mekk2-deficient and wild-type mice. However, Mekk2(-/-) T-cell proliferation was augmented in response to anti-CD3 monoclonal antibody (MAb) stimulation, and these T cells produced more interleukin 2 and gamma interferon than did the wild-type T cells, suggesting that MEKK2 may be involved in controlling the strength of T-cell receptor (TCR) signaling. Consistently, Mekk2(-/-) thymocytes were more susceptible than wild-type thymocytes to anti-CD3 MAb-induced cell death. Furthermore, TCR-mediated c-Jun N-terminal kinase activation was not blocked but moderately enhanced in Mekk2(-/-) T cells. Neither extracellular signal-regulated kinase nor p38 MAPK activation was affected in Mekk2(-/-) T cells. In conclusion, we found that MEKK2 may be required for controlling the strength of TCR/CD3 signaling.
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Zijian
Z
Guo
Gavin
G
Clydesdale
Jinke
J
Cheng
Kihwan
K
Kim
Lin
L
Gan
David J
DJ
McConkey
Stephen E
SE
Ullrich
Yuan
Y
Zhuang
Bing
B
Su
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005434:Flow Cytometry; D018390:Gene Targeting; D005938:Glucocorticoids / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology / Q000528:radiation effects; D013950:Thymus Gland / Q000166:cytology; D014466:Ultraviolet Rays
D000906:Antibodies; D005938:Glucocorticoids; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D003907:Dexamethasone; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482619:Map3k2 protein, mouse