title: BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival.
abstract: B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers.
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research London, London NW7 1AA, England, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jacque
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research London, London NW7 1AA, England, UK.
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research London, London NW7 1AA, England, UK.
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.affiliation: Division of Immune Cell Biology, MRC National Institute for Medical Research London, London NW7 1AA, England, UK steve.ley@crick.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D001854:Bone Marrow Cells / Q000166:cytology; D002470:Cell Survival; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D048671:MAP Kinase Kinase 5 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D053264:B-Cell Activating Factor; C096816:BCL2-related protein A1; C579094:Mcl1 protein, mouse; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C505720:Tnfsf13b protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C578399:Map2k5 protein, mouse