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

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 PKCδ (nPKCδ) 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 nPKCδ inhibitor rottlerin blocks CREB phosphorylation following BCR cross-linking. Bryostatin 1 selectively prevents nPKCδ depletion by phorbol 12-myristate 13-acetate when coapplied, coincident with protection of BCR-induced CREB phosphorylation. Ectopic expression of a kinase-inactive nPKCδ blocks BCR-induced CREB phosphorylation in A20 B cells. In addition, BCR-induced CREB phosphorylation is significantly diminished in nPKCδ-deficient splenic B cells in comparison with wild type mice. Consistent with the essential role for Bruton's tyrosine kinase and phospholipase Cγ2 in mediating PKC activation, Bruton's tyrosine kinase- and phospholipase Cγ2-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 nPKCδ. Taken together, these results suggest a model in which BCR engagement leads to the phosphorylation of CREB via a signaling pathway that requires nPKCδ and p90 RSK in mature B cells. 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 PKCδ (nPKCδ) 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 nPKCδ inhibitor rottlerin blocks CREB phosphorylation following BCR cross-linking. Bryostatin 1 selectively prevents nPKCδ depletion by phorbol 12-myristate 13-acetate when coapplied, coincident with protection of BCR-induced CREB phosphorylation. Ectopic expression of a kinase-inactive nPKCδ blocks BCR-induced CREB phosphorylation in A20 B cells. In addition, BCR-induced CREB phosphorylation is significantly diminished in nPKCδ-deficient splenic B cells in comparison with wild type mice. Consistent with the essential role for Bruton's tyrosine kinase and phospholipase Cγ2 in mediating PKC activation, Bruton's tyrosine kinase- and phospholipase Cγ2-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 nPKCδ. Taken together, these results suggest a model in which BCR engagement leads to the phosphorylation of CREB via a signaling pathway that requires nPKCδ and p90 RSK in mature B cells. Signaling through the B cell antigen receptor (BCR) 1The abbreviations used are: BCR, B cell antigen receptor; Ab, antibody; anti-Ig, F(ab′)2 fragments of anti-mouse IgM; BLNK, adaptor protein B cell linker protein; Btk, Bruton's tyrosine kinase; cPKC, conventional PKC; CRE, cAMP-response element; CREB, cAMP-response element-binding protein; EMSA, electrophoretic mobility shift assay; MAPK, mitogen-activated protein kinase; MSK-1, mitogen-activated stress kinase 1; nPKC, novel PKC; nPKCδ, novel PKCδ; PKC, protein kinase C; PLCγ, phospholipase Cγ; PMA, phorbol 12-myristate 13-acetate; RSK, ribosomal S6 kinase; CaMK II, calmodulin kinase II; MBP, maltose-binding protein; Bis A, bistratene A. is required throughout B cell development and peripheral maturation (1Cariappa A. Pillai S. Curr. Opin. Immunol. 2002; 14: 241-249Crossref PubMed Scopus (103) Google Scholar, 2Lam K.-P. Kuhn R. Rajewsky K. Cell. 1997; 90: 1073-1083Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar). BCR signaling requires the activities of multiple nonreceptor protein-tyrosine kinases, including Syk, Bruton's tyrosine kinase (Btk), and Src family kinases and the lipid kinase, phosphatidylinositol 3-kinase (3Craxton A. Otipoby K.L. Jiang A. Clark E.A. Adv. Immunol. 1999; 73: 79-152Crossref PubMed Google Scholar). Btk plays an integral role in transducing BCR signals, because mutations in the gene encoding btk result in the B cell deficiencies, X-linked immunodeficiency in the mouse and X-linked agammaglobulinemia in humans (reviewed in Ref. 4Satterthwaite A.B. Witte O.N. Immunol. Rev. 2000; 175: 120-127Crossref PubMed Google Scholar). 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PubMed Scopus Google that CREB activity is following BCR cross-linking is by that CREB plays an role in B cell and of CREB is for activation of the K. J. Immunol. Google Scholar, N. R. N. J. Immunol. Google Scholar). In a CREB a substitution at and survival in to BCR cross-linking Wu J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In to the CREB phosphorylation is for gene expression in B cells E. Cell. PubMed Scopus Google Scholar). In addition, CREB has been in the of gene in B cell including the II and J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. Immunol. 2000; PubMed Scopus Google Scholar, S. Cell. 1999; PubMed Scopus Google Scholar, A. J. Immunol. PubMed Scopus Google Scholar, P. J. Immunol. 1995; Google Scholar). the of CREB phosphorylation in B cell the of of CREB by the BCR. of these to the role of PKC in the BCR to CREB phosphorylation. a a phorbol ester PKC activity to required for BCR-induced CREB phosphorylation in B cells J. 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PubMed Scopus Google Scholar). these suggest an of PKC to CREB phosphorylation, the identity of the PKC has not been the signaling that link PKC activity to CREB phosphorylation to In the of pharmacological and of nPKCδ-deficient A20 B cells a kinase-inactive nPKCδ, and B cell in to the signaling that CREB phosphorylation in mature B cells. results that BCR cross-linking CREB phosphorylation via a signaling pathway nPKCδ and p90 and from and RSK from Signaling and anti-mouse from from The and from Bryostatin and rottlerin from inhibitor phorbol 12-myristate 13-acetate and from in at that the of in F(ab′)2 fragments of anti-mouse or from from The from from The and from and of B murine B from of The murine A20 B by A20 cell by at a of of of to the A20 cells with wild type nPKCδ or a nPKCδ a substitution in the that in a kinase-inactive nPKCδ S. P. P. J. J. Cell. 1999; PubMed Scopus Google Scholar). in The murine B cell in in a at The B cell by E. A. Clark of of and and in and Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. K. I. M. A. Immunity. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). and from The and at for and at in with of and B cells by depletion of cells with by K. J. Immunol. Google Scholar). cells and cells by on M. B from I. K. M. A. 2002; PubMed Scopus Google the of on has been I. K. M. A. 2002; PubMed Scopus Google Scholar). The B cell in with and B cells in a at cells in and 1 1 1 and with inhibitor protein by through an and to The in and for and with at 1 in The in and with a of or anti-mouse for and by by a and In B cells by in and in a 1 1 1 1 1 1 and for at with RSK that activated p90 RSK Signaling with a of protein and with at for in of kinase and of protein The by and the by CREB on Ser-133 by with In nPKCδ kinase activity with the following from B cell used to 1 in of kinase with of for at The kinase by the of and by The by by and in a K. J. Immunol. Google Scholar). in a of and of protein with and of with by kinase the through a and to the of to the the wild type and to and B CREB or CREB the wild type whereas the to E. Cell. PubMed Scopus Google Scholar). by including in the of or BCR-induced of CREB on to the for a in BCR-induced CREB phosphorylation on The PKC in mouse B cells and activated by BCR-induced and and and I. K. M. A. 2002; PubMed Scopus Google Scholar, J. Davidson S. J. Immunol. Google Scholar, J. PubMed Scopus Google Scholar). B cells for with in to cells of and with or a for the of PMA, B cells also for with of the of B cells with to a block in BCR-induced CREB phosphorylation with of to B cell to CREB phosphorylation with The of CREB phosphorylation to depletion of CREB by CREB, CREB phosphorylation in B cells with or the of to PKC found that the of nPKCδ and by PMA, not nPKCδ and results for the and not of nPKCδ and on BCR-induced CREB in B the PKC to BCR-induced CREB phosphorylation, of PKCs for to CREB phosphorylation. is a inhibitor of and G. M.G. G. J. Full Text PDF PubMed Google Scholar, P. P. M. P. E. F. J. Full Text PDF PubMed Google Scholar). of splenic B cells with from to not CREB phosphorylation the used results with the inhibitor not The of in that phosphorylation on an at in on G. J. Cell. 1999; PubMed Google Scholar). Taken with the in these to a role for in the BCR to CREB the in B nPKCδ the of expression and is on and in to BCR cross-linking I. K. M. A. 2002; PubMed Scopus Google Scholar, Immunol. 1999; PubMed Scopus Google Scholar). nPKCδ activity is for BCR-induced CREB phosphorylation, splenic B cells with a inhibitor of nPKCδ M. Muller K. R. G. F. PubMed Scopus Google Scholar). between and rottlerin BCR-induced CREB phosphorylation in splenic B cells from or a found that BCR-induced nPKCδ activity by of splenic B cells with rottlerin suggest that nPKCδ activity is required for BCR-induced CREB phosphorylation. for a role of nPKCδ in CREB phosphorylation, the activator of nPKCδ, bistratene A sufficient to CREB phosphorylation. Bis A is a from and has been to selectively nPKCδ in vivo at between and G. S. R. M. Exp. PubMed Scopus Google Scholar). of splenic B cells with Bis A to a and in CREB phosphorylation Bis A not the of protein Bis A also CREB phosphorylation in splenic B cells from not BCR-induced CREB phosphorylation is by the nPKCδ and by activation of nPKCδ in the absence of BCR cross-linking. Bryostatin 1 nPKCδ from with BCR-induced CREB the the of a ester activator of on CREB phosphorylation. that of cells to 1 at between and 1 results in the protection of nPKCδ, not from depletion when J. Full Text PDF PubMed Google Scholar, Google Scholar). 1 of BCR-induced CREB phosphorylation following depletion of splenic B cells with or with the of and In with the in of splenic B cells with to a block in CREB phosphorylation at the CREB phosphorylation in B cells with the of and In not also found that 1 BCR-induced CREB phosphorylation from in the mature B cell A20 and The of nPKCδ in B cells with the of 1 significantly in comparison to that nPKCδ from depletion the of which not to not by or the of and 1 The and in B cells in comparison to that these not by 1 in of a role for nPKCδ in BCR-induced CREB phosphorylation. BCR-induced CREB in nPKCδ-deficient B directly nPKCδ is in phosphorylation of CREB on CREB phosphorylation in splenic B cells from wild type and I. K. M. A. 2002; PubMed Scopus Google Scholar). of the BCR on nPKCδ-deficient B cells in a significantly diminished of CREB phosphorylation in comparison to wild type B cells The CREB phosphorylation in nPKCδ-deficient B cells to a in the of CREB protein in B cells to wild type is that I. K. M. A. 2002; PubMed Scopus Google Scholar, A. K. S. Jiang M. S. S. K.L. 2002; PubMed Scopus Google of and in to BCR cross-linking in B cells that is with wild phosphorylation of CREB following BCR in B cells not a in BCR signaling to for nPKCδ in the of CREB phosphorylation by the BCR, mature A20 B cell that wild type nPKCδ or a kinase-inactive nPKCδ The protein an amino acid substitution in the which is for S. P. P. J. J. Cell. 1999; PubMed Scopus Google Scholar). expression of wild type nPKCδ in A20 B cells in in an of CREB phosphorylation in comparison to the A20 B cells A20 and of wild type nPKCδ A20 B cells with or in CREB phosphorylation and PMA, In expression of in A20 B cells in a near-complete of and CREB phosphorylation The of CREB between the A20 cell a role for nPKCδ in the BCR to CREB phosphorylation. BCR-induced of CREB Btk and is the of CREB phosphorylation by signaling to the BCR. The results suggest that CREB phosphorylation is on nPKCδ. that is for CREB phosphorylation, that activation results in the of that to and nPKCδ activated by of which of and M. J. 1999; PubMed Scopus Google Scholar, S. N. N. Cell. PubMed Google Scholar). is for BCR-induced CREB phosphorylation, of B cells in M. J. Exp. Med. 1995; PubMed Scopus Google Scholar, M. J. Exp. Med. PubMed Scopus Google Scholar). B cells CREB phosphorylation in to BCR cross-linking in comparison to the B cell and In with of vivo splenic B cells with 1 a in in BCR-induced CREB phosphorylation in comparison to B cells We also found that B cells in Btk, a key activator of to induce CREB phosphorylation in to and B cells in Syk, which to activation, also to CREB in to BCR cross-linking and that these results to CREB or in protein for the of CREB and in of the B cell phosphorylation at in the activation of nPKCδ is to a role in activation and by the B cell I. K. M. A. 2002; PubMed Scopus Google Scholar, M. J. 1999; PubMed Scopus Google BCR-induced phosphorylation of nPKCδ at the activation in B cells. in BCR cross-linking on the B cell an in nPKCδ phosphorylation at with a in mouse splenic B cells I. K. M. A. 2002; PubMed Scopus Google Scholar). In B cells in Btk, or a absence of BCR-induced phosphorylation of nPKCδ on for p90 RSK in nPKCδ to CREB to signaling that to link nPKCδ to CREB phosphorylation. protein kinases been that CREB kinases, including MSK-1, p90 RSK, CaMK and (reviewed in Rev. 1999; PubMed Scopus Google and W.N. J. Full Text Full Text PDF PubMed Scopus Google Scholar, E. E. K. J. Immunol. PubMed Scopus Google Scholar, P. G. J. W.N. Exp. PubMed Scopus Google Scholar). K. J. Immunol. Google Scholar, J. Immunol. 1995; Google Scholar, Cell. Immunol. PubMed Scopus Google of activity and in mediating CREB phosphorylation in mature B following BCR cross-linking. We found that of or splenic B cells with to an in phosphorylation on the activation however, the in phosphorylation not on nPKCδ activity not In addition, to activation of in to of splenic B cells or the B cell not J. Immunol. 2000; PubMed Scopus Google Scholar). in the activation of p90 RSK in splenic B cells and B cell following BCR cross-linking. of p90 RSK on the activation which has been to with activity N. J. P. J. Full Text Full Text PDF PubMed Scopus Google at and following BCR in B cells results splenic B cells p90 RSK phosphorylation is on nPKCδ, B cells or splenic B cells with and p90 RSK phosphorylation on by in rottlerin BCR-induced p90 RSK phosphorylation at the in splenic and B cells. In addition, of B cells with which to to BCR-induced p90 RSK phosphorylation the of p90 RSK phosphorylation in splenic B cells in with the no effect on CREB phosphorylation in splenic B cells, the of CREB phosphorylation in the B cell and Consistent with these A20 B cells a kinase-inactive nPKCδ to p90 RSK in to BCR engagement or whereas A20 B cells, whereas wild type nPKCδ A20 B cells p90 RSK phosphorylation A20 and We that expression of wild type nPKCδ in A20 B cells in in an of p90 RSK phosphorylation in comparison to the A20 B cells We p90 RSK of directly CREB on these p90 from B cells or splenic B cells and for phosphorylation of a protein in p90 from B cell in of kinase whereas p90 from B cells on Ser-133 not kinase activity of B cells with rottlerin p90 CREB phosphorylation Taken together, these suggest that p90 RSK phosphorylates CREB on Ser-133 and downstream of nPKCδ in mature B cells. for nPKCδ in BCR-induced CREB at the gene is for B cell survival and is by CREB that to a in the gene E. Cell. PubMed Scopus Google Scholar). The signaling pathway BCR-induced gene expression via CREB has not been however, activation of the gene in to phorbol of B cells that a activity is E. Cell. PubMed Scopus Google Scholar). We to nPKCδ to BCR-induced CREB phosphorylation to the gene In from and B cells, and activity to a the gene by electrophoretic mobility shift in a single with the The in that with a which to of activity E. Cell. PubMed Scopus Google Scholar). with from B cells the of CREB in the activity by the a of a not or the nPKCδ required for phosphorylation of CREB at the vivo splenic B cells with of rottlerin and in or with of B cells with rottlerin in a of Ser-133 phosphorylation of CREB at the by a in the of The in CREB phosphorylation to of CREB, the of CREB to the not by rottlerin at the used a role for nPKCδ, B cells with Bis A for and and by The in that Bis A is sufficient to Ser-133 phosphorylation of CREB to the Bis A not the of CREB to the that of nPKCδ by with rottlerin the and BCR-induced expression in splenic B cells results with the by rottlerin of CREB Ser-133 phosphorylation at the gene of CREB by phosphorylation on Ser-133 an in the signaling pathway by BCR cross-linking. of CREB is for the of in B cell and survival N. J. Full Text Full Text PDF PubMed Scopus Google Scholar, K. J. Immunol. Google Scholar, J. Immunol. 1995; Google Scholar, F. J. S. N. J. Immunol. 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In the the signaling pathway for CREB phosphorylation in vivo splenic B cells. is with a model BCR-induced CREB phosphorylation on Ser-133 is by a pathway that requires the novel nPKCδ. The of model is by The nPKCδ inhibitor blocks CREB phosphorylation. with BCR signaling to nPKCδ and Ref. Immunol. 1999; PubMed Scopus Google Scholar). We also that a that is used in with to the role of nPKCδ, CREB phosphorylation from with protection of nPKCδ from depletion J. Full Text PDF PubMed Google Scholar, Google Scholar). Consistent with these bistratene A, a activator of nPKCδ, when to B cells in the absence of BCR cross-linking is sufficient to CREB phosphorylation. also by that expression of a kinase-inactive nPKCδ in mature A20 B cells blocks BCR-induced CREB phosphorylation on We also that BCR-induced CREB phosphorylation is significantly diminished in splenic B cells from in comparison to wild type mice. CREB phosphorylation in nPKCδ-deficient splenic B cells is not following BCR cross-linking the of a pathway that to CREB phosphorylation. pathway in B cells or a pathway in is not BCR-induced CREB phosphorylation not by rottlerin of splenic B cells. that a activity is for the CREB phosphorylation that the inhibitor not block BCR signaling to CREB phosphorylation. the of phosphorylation by an on activity G. J. Cell. 1999; PubMed Google Scholar, W.N. J. Full Text Full Text PDF PubMed Scopus Google Scholar). not nPKCδ has been to CREB phosphorylation in cells E. E. K. J. Immunol. PubMed Scopus Google Scholar). the that to BCR-induced CREB phosphorylation in mature B cells. expression of a kinase-inactive nPKCδ in A20 B cells in a of BCR-induced CREB phosphorylation, that CREB phosphorylation is a nPKCδ pathway in A20 B cells. The in CREB phosphorylation between A20 B cells and splenic B cells CREB phosphorylation in to BCR in the cell used B and B the to a for nPKCδ in the BCR to CREB Ser-133 phosphorylation. The targets of nPKCδ in B cells however, a has that nPKCδ gene expression in to BCR cross-linking P. G. J. W.N. Exp. PubMed Scopus Google Scholar). E. Cell. PubMed Scopus Google that phosphorylation of CREB a signaling in the activation of the gene and that activation is a PKC We that when vivo splenic B cells with is a in the of CREB to the gene bistratene A of splenic B cells is sufficient to induce Ser-133 phosphorylation of CREB to the In with these of nPKCδ with rottlerin blocks BCR-induced results the that nPKCδ plays a role in gene expression in mature B cells. to the of gene expression by nPKCδ in the of BCR signaling. results also for the p90 RSK in CREB phosphorylation in mature B cells. In that p90 of directly an protein on p90 RSK downstream of nPKCδ is by in which of splenic B cells with rottlerin blocks BCR-induced p90 RSK phosphorylation on the activation N. J. P. J. Full Text Full Text PDF PubMed Scopus Google Scholar). that rottlerin has been in the of of rottlerin required in comparison to M. J. 1999; PubMed Scopus Google Scholar). that rottlerin blocks the kinase activity of nPKCδ and however, these nPKCδ is in B cells A. S. N. A.B. Cell. PubMed Scopus Google Scholar). a of in BCR-induced p90 RSK activation, that expression of a kinase-inactive nPKCδ in A20 B cells results in a of BCR-induced p90 RSK phosphorylation on is that of the p90 RSK family been CREB kinases J. PubMed Scopus Google Scholar). In the of the p90 RSK in CREB phosphorylation is by the that CREB phosphorylation is in from which mutations in the gene encoding S. S. E. I. P. A. 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The absence of CREB phosphorylation in B cells with of BCR-induced CREB phosphorylation in B cells with the inhibitor suggest that is essential for CREB phosphorylation. with these a Immunol. 1999; PubMed Scopus Google that prevents of nPKCδ in to BCR cross-linking in B cells. of BCR requires and tyrosine phosphorylation by Btk Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. K. I. M. A. Immunity. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. J. Immunol. 1999; Google Scholar, S. A. M. K. M. S. 1999; PubMed Google Scholar, M. J. Exp. Med. PubMed Scopus Google Scholar, M. A. J. PubMed Scopus Google Scholar). In with the role of Btk in that B cells not BCR-induced CREB phosphorylation in comparison to wild type B cells. We also that BCR-induced phosphorylation of nPKCδ on is in of the B cells. that the of the signaling block is for the of CREB phosphorylation by the BCR. In the a role for nPKCδ in BCR signaling to The with a model in which BCR engagement on mature B leads to the phosphorylation of CREB via a signaling pathway that requires nPKCδ, and p90 We of for the bistratene A. We also E. and for with of the