Article abstract
Nature Immunology 8, 57 - 63 (2006)
Published online: 3 December 2006 | doi:10.1038/ni1421
Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production
Ewen Gallagher1,6, Thomas Enzler1,6, Atsushi Matsuzawa1,6, Amy Anzelon-Mills2, Dennis Otero3, Ryan Holzer1, Edith Janssen4, Min Gao1,5 & Michael Karin1
Abstract
Mice lacking activity of the kinase MEKK1 ('Map3k1
KD' 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 Map3k1KD 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 Map3k1KD 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.
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California 92093-0723, USA.
- Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
- Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
- La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
- Present address: Pharmacopeia Drug Discovery, Cranbury, New Jersey 08512, USA.
- These authors contributed equally to this work.
Correspondence to: Michael Karin1 e-mail: karinoffice@ucsd.edu
