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J. Biol. Chem., Vol. 279, Issue 29, 30123-30132, July 16, 2004

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

Joseph T. Blois, Jennifer M. Mataraza, Ingrid Mecklenbraüker, Alexander Tarakhovsky, and Thomas C. Chiles¶

From the Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467 and Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10021

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 (nPKC) activator bistratene A is sufficient to induce CREB phosphorylation in murine splenic B cells. The pharmacological inhibitor Gö6976, which targets conventional PKCs and PKCµ, has no effect on CREB phosphorylation, whereas the nPKC inhibitor rottlerin blocks CREB phosphorylation following BCR cross-linking. Bryostatin 1 selectively prevents nPKC depletion by phorbol 12-myristate 13-acetate when coapplied, coincident with protection of BCR-induced CREB phosphorylation. Ectopic expression of a kinase-inactive nPKC blocks BCR-induced CREB phosphorylation in A20 B cells. In addition, BCR-induced CREB phosphorylation is significantly diminished in nPKC-deficient splenic B cells in comparison with wild type mice. Consistent with the essential role for Bruton's tyrosine kinase and phospholipase C2 in mediating PKC activation, Bruton's tyrosine kinase- and phospholipase C2-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. Taken together, these results suggest a model in which BCR engagement leads to the phosphorylation of CREB via a signaling pathway that requires nPKC and p90 RSK in mature B cells.

Received for publication, March 11, 2004 , and in revised form, May 6, 2004.

^* This work was supported by Public Health Service Grant AI34586. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biology, Boston College, 414 Higgins Hall, Chestnut Hill, MA 02467. Tel.: 617-552-0840; Fax: 617-552-3130; E-mail: ChilesT{at}bc.edu.

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