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.
D000123:Acetyltransferases / Q000502:physiology; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1