title: PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.
abstract: Plasma cell differentiation is initiated by antigen stimulation of the B cell receptor (BCR) and is regulated by BLIMP1. Prior to the stimulation of BCR, BLIMP1 is suppressed by PAX5, which is a key transcriptional repressor that maintains B cell identity. The upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed after the BCR stimulation. These events are considered to trigger plasma cell differentiation; however, the mechanisms responsible currently remain unclear. We herein demonstrated that the BCR signaling component, SYK, caused PAX5 tyrosine phosphorylation in vitro and in cells. Transcriptional repression on the BLIMP1 promoter by PAX5 was attenuated by this phosphorylation. The BCR stimulation induced the phosphorylation of SYK, tyrosine phosphorylation of PAX5, and up-regulation of BLIMP1 mRNA expression in B cells. The tyrosine phosphorylation of PAX5 co-operatively functioned with PAX5 serine phosphorylation by ERK1/2, which was our previous findings, to cancel the PAX5-dependent repression of BLIMP1. This co-operation may be a trigger for plasma cell differentiation. These results imply that PAX5 phosphorylation by a BCR signal is the initial event in plasma cell differentiation.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Inagaki
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: bun-hy@med.nagoya-u.ac.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Hirano
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Morishita
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D051757:PAX5 Transcription Factor / Q000378:metabolism*; D010766:Phosphorylation; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D000072377:Syk Kinase / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011947:Receptors, Antigen, B-Cell; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D014443:Tyrosine; D000074462:Positive Regulatory Domain I-Binding Factor 1; C000606896:SYK protein, human; D000072377:Syk Kinase
keywords: BLIMP1; PAX5; Phosphorylation; Plasma cell differentiation; SYK