RRC ID 73231
Author Blois JT, Mataraza JM, Mecklenbraüker I, Tarakhovsky A, Chiles TC.
Title B cell receptor-induced cAMP-response element-binding protein activation in B lymphocytes requires novel protein kinase Cdelta.
Journal J Biol Chem
Abstract The cAMP-response element-binding protein (CREB) is activated by phosphorylation on Ser-133 and plays a key role in the proliferative and survival responses of mature B cells to B cell receptor (BCR) signaling. The signal link between the BCR and CREB activation depends on a phorbol ester (phorbol 12-myristate 13-acetate)-sensitive protein kinase C (PKC) activity and not protein kinase A or calmodulin kinase; however, the identity and role of the PKC(s) activity has not been elucidated. We found the novel PKCdelta (nPKCdelta) activator bistratene A is sufficient to induce CREB phosphorylation in murine splenic B cells. The pharmacological inhibitor Gö6976, which targets conventional PKCs and PKCmu, has no effect on CREB phosphorylation, whereas the nPKCdelta inhibitor rottlerin blocks CREB phosphorylation following BCR cross-linking. Bryostatin 1 selectively prevents nPKCdelta depletion by phorbol 12-myristate 13-acetate when coapplied, coincident with protection of BCR-induced CREB phosphorylation. Ectopic expression of a kinase-inactive nPKCdelta blocks BCR-induced CREB phosphorylation in A20 B cells. In addition, BCR-induced CREB phosphorylation is significantly diminished in nPKCdelta-deficient splenic B cells in comparison with wild type mice. Consistent with the essential role for Bruton's tyrosine kinase and phospholipase Cgamma2 in mediating PKC activation, Bruton's tyrosine kinase- and phospholipase Cgamma2-deficient B cells display defective CREB phosphorylation by the BCR. We also found that p90 RSK directly phosphorylates CREB on Ser-133 following BCR cross-linking and is positioned downstream of nPKCdelta. Taken together, these results suggest a model in which BCR engagement leads to the phosphorylation of CREB via a signaling pathway that requires nPKCdelta and p90 RSK in mature B cells.
Volume 279(29)
Pages 30123-32
Published 2004-7-16
DOI 10.1074/jbc.M402793200
PII S0021-9258(19)71024-2
PMID 15138267
MeSH Acetamides / pharmacology Acetophenones / pharmacology Animals B-Lymphocytes / metabolism* Benzopyrans / pharmacology Binding Sites Blotting, Western Bryostatins Calcium-Calmodulin-Dependent Protein Kinases / metabolism Carbazoles / pharmacology Cell Division Cross-Linking Reagents / pharmacology Cyclic AMP Response Element-Binding Protein / metabolism* Cyclic AMP-Dependent Protein Kinases / metabolism Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Indoles / pharmacology Lactones / pharmacology Macrolides Mice Mice, Inbred BALB C Mice, Inbred CBA Mitogens Phosphorylation Promoter Regions, Genetic Protein Isoforms Protein Kinase C / metabolism* Protein Kinase C-delta Protein Structure, Tertiary Pyrans / pharmacology Receptors, Antigen, B-Cell / metabolism* Ribosomal Protein S6 Kinases, 90-kDa / metabolism Serine / chemistry Signal Transduction Spiro Compounds / pharmacology Tetradecanoylphorbol Acetate Time Factors
IF 4.238
Resource
Human and Animal Cells PLC-γ2^(-) DT40(RCB1469) Btk^(-) DT40(RCB1468) Syk^(-) DT40(RCB1470)