Stimulation of Elk1 Transcriptional Activity by Mitogen-activated Protein Kinases Is Negatively Regulated by Protein Phosphatase 2B (Calcineurin)

Cellular calcium (Ca2+) and the Ca2+-binding protein calmodulin (CaM) regulate the activities of Ca2+/CaM-dependent protein kinases and protein phosphatase 2B (calcineurin). Functional interactions between CaM kinases and mitogen-activated protein (MAP) kinases were described. In this report, we describe cross-talk between calcineurin and mitogen-activated protein kinase signaling. Calcineurin was found to specifically down-regulate the transcriptional activity of transcription factor Elk1, following stimulation of this activity by the ERK, Jun N-terminal kinase, or p38 MAP kinase pathways. Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity. Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1. The cross-talk between calcineurin and MAP kinases is of physiological significance as low doses of Ca2+ ionophore which by themselves are insufficient for c-fos induction can actually inhibit induction of c-fos expression by activators of MAP kinases. Thus through the effect of calcineurin on Elk1 phosphorylation, Ca2+ can have a negative effect on expression of Elk1 target genes. This mechanism explains why different levels of intracellular Ca2+ can result in very different effects on gene expression. Cellular calcium (Ca2+) and the Ca2+-binding protein calmodulin (CaM) regulate the activities of Ca2+/CaM-dependent protein kinases and protein phosphatase 2B (calcineurin). Functional interactions between CaM kinases and mitogen-activated protein (MAP) kinases were described. In this report, we describe cross-talk between calcineurin and mitogen-activated protein kinase signaling. Calcineurin was found to specifically down-regulate the transcriptional activity of transcription factor Elk1, following stimulation of this activity by the ERK, Jun N-terminal kinase, or p38 MAP kinase pathways. Expression of constitutively activated calcineurin or activation of endogenous calcineurin by Ca2+ ionophore decreased the phosphorylation of Elk1 at sites that positively regulate its transcriptional activity. Calcineurin specifically dephosphorylates Elk1 at phosphoserine 383, a site whose phosphorylation by MAP kinases makes a critical contribution to the enhanced transcriptional activity of Elk1. The cross-talk between calcineurin and MAP kinases is of physiological significance as low doses of Ca2+ ionophore which by themselves are insufficient for c-fos induction can actually inhibit induction of c-fos expression by activators of MAP kinases. Thus through the effect of calcineurin on Elk1 phosphorylation, Ca2+ can have a negative effect on expression of Elk1 target genes. This mechanism explains why different levels of intracellular Ca2+ can result in very different effects on gene expression. The second messenger Ca2+ plays a critical regulatory role in a variety of physiological processes in many different cell types (1Bading H. Hardingham G.E. Johnson C.M. Chawla S. Biochem. Biophys. Res. Commun. 1997; 236: 541-543Crossref PubMed Scopus (76) Google Scholar, 2Malviya A.N. Rogue P.J. Cell. 1998; 92: 17-23Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). 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The Ca2+-CaM complex binds to and modulates the activities of multiple key signal-transducing enzymes, including Ca2+/CaM-dependent protein kinases (CaM-K) (4Tokumitsu H. Soderling T.R. J. Biol. Chem. 1996; 271: 5617-5622Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar,5Wayman G.A. Tokumitsu H. Soderling T.R. J. Biol. Chem. 1997; 272: 16073-16076Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) and the Ca2+/CaM-dependent protein serine/threonine phosphatase calcineurin (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar, 7Lohse D.L. Denu J.M. Dixon J.E. Structure. 1995; 3: 987-990Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). The CaM kinases have several substrates involved in transcriptional control, such as CREB (cAMP-responsive element binding protein) (8Cruzalegui F.H. Means A.R. J. Biol. 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PubMed Scopus Google Scholar). a in intracellular Ca2+ have a negative effect on c-fos transcription through activation of a in c-fos transcription through activation of and as in of with 1 is for induction of c-fos transcription intracellular Ca2+ to a for CaM kinase that of Ca2+ is for of c-fos induction by that MAPK signaling is for activation of as by the of Elk1. a mechanism the regulatory of Ca2+ In to its regulatory effect on Elk1 at the c-fos or calcineurin in the Calcineurin is to a cytoplasmic protein (6Guerini D. Biochem. Biophys. Res. Commun. 1997; 235: 271-275Crossref PubMed Scopus (141) Google Scholar). no nuclear A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). in the of activated T A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). was that after calcineurin dephosphorylates to the by of its with this transcription factor A. J. A. Acad. Sci. S. A. 1996; PubMed Scopus Google Scholar). 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