Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production.
Mice lacking activity of the kinase MEKK1 ('Map3k1(deltaKD)' mice) have defective activation of the kinase Jnk and increased production of T helper type 2 cytokines after T cell receptor ligation. Here we show that Map3k1(deltaKD) mice had defective germinal center formation and diminished production of antibodies recognizing thymus-dependent antigens. Those defects were B cell intrinsic, as MEKK1 was necessary for CD40-mediated activation of the kinases Jnk and p38 and transcription factor c-Jun, as well as for expression of cyclin D2 and activation-induced deaminase. MEKK1 was recruited to CD40 and adaptor molecule TRAF2 after CD40 ligation, and Map3k1(deltaKD) B cells were hypoproliferative after CD40 stimulation. Our data emphasize that MEKK1 is an essential component of signaling cascades needed for thymus-dependent antigen-induced B cell proliferation and antibody production.
Gallagher
Ewen
E
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California 92093-0723, USA.
Enzler
Thomas
T
Matsuzawa
Atsushi
A
Anzelon-Mills
Amy
A
Otero
Dennis
D
Holzer
Ryan
R
Janssen
Edith
E
Gao
Min
M
Karin
Michael
M
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D018858:Germinal Center / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019013:CD40 Antigens; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4