B Cell Receptor-induced cAMP-response Element-binding Protein Activation in B Lymphocytes Requires Novel Protein Kinase Cδ

• Published in: The Journal of biological chemistry 2004-07, Vol.279 (29), p.30123-30132
• Main Authors: Blois, Joseph T., Mataraza, Jennifer M., Mecklenbraüker, Ingrid, Tarakhovsky, Alexander, Chiles, Thomas C.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M402793200

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 PKC delta (nPKC delta ) activator bistratene A is sufficient to induce CREB phosphorylation in murine splenic B cells. The pharmacological inhibitor Goe6976, which targets conventional PKCs and PKC mu , has no effect on CREB phosphorylation, whereas the nPKC delta inhibitor rottlerin blocks CREB phosphorylation following BCR cross- linking. Bryostatin 1 selectively prevents nPKC delta depletion by phorbol 12- myristate 13-acetate when coapplied, coincident with protection of BCR-induced CREB phosphorylation. Ectopic expression of a kinase-inactive nPKC delta blocks BCR- induced CREB phosphorylation in A20 B cells. In addition, BCR-induced CREB phosphorylation is significantly diminished in nPKC delta -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 nPKC delta . Taken together, these results suggest a model in which BCR engagement leads to the phosphorylation of CREB via a signaling pathway that requires nPKC delta and p90 RSK in mature B cells.