title: MK5 activates Rag transcription via Foxo1 in developing B cells.
abstract: Foxo1 is a critical, direct regulator of Rag (recombination activating gene) transcription during B cell development and is thus essential for the generation of a diverse repertoire of antigen receptors. Although Foxo1 regulation has been widely studied in many cell types, pathways regulating Foxo1 in B cells have not been fully elucidated. By screening a panel of Foxo1 mutants, we identified serine 215 on Foxo1 as a novel phosphorylation site that is essential for the activation of Rag transcription. Mutation of S215 strongly attenuated transactivation of Rag but did not affect most other Foxo1 target genes. We show that MK5, a MAPK-activated protein kinase, is a previously unidentified upstream regulator of Foxo1. MK5 was necessary and sufficient to activate Rag transcription in transformed and primary pro-B cells. Together, our experiments show that MK5 positively regulates Rag transcription via phosphorylation of Foxo1 in developing B cells.
authors.affiliation: Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Kwan T
authors.initials: KT
authors.lastname: Chow
authors.forename: Greg A
authors.initials: GA
authors.lastname: Timblin
authors.forename: Sarah M
authors.initials: SM
authors.lastname: McWhirter
authors.forename: Mark S
authors.initials: MS
authors.lastname: Schlissel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002461:Cell Line, Transformed; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D016654:Genes, RAG-1; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001549:Benzamides; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015534:Trans-Activators; D012694:Serine; C111049:MAP-kinase-activated kinase 5; D000068877:Imatinib Mesylate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt