Convergence of MAP kinase pathways on the ternary complex factor Sap-1a.
The serum response element (SRE), which is pivotal for transcriptional up-regulation of the c-fos protooncogene, is constitutively occupied by a protein complex comprising the serum response factor and a ternary complex factor (TCF). Phosphorylation of the TCFs Elk-1 and Sap-1a by the ERK and JNK subclasses of MAP kinases triggers c-fos transcription. We demonstrate here that Elk-1 is barely activated by a third subclass of MAP kinases (p38), most likely because the critical residues Ser383 and Ser389 are poorly phosphorylated by p38 MAP kinase. In contrast, the TCF Sap-1a is efficiently phosphorylated by p38 MAP kinase in vitro and in vivo on the homologous residues Ser381 and Ser387. Mutation of these sites to alanine severely reduces c-fos SRE-dependent transcription mediated by Sap-1a and p38 MAP kinase. Thus, Sap-1a may be an important target for mitogens, stress and apoptotic signals to elicit a nuclear response. However, signaling from p38 MAP kinase to Sap-1a or from Sap-1a to the basal transcription machinery does not occur in all cell types nor at promoters other than the c-fos SRE, which may ensure the specificity of signaling.
Janknecht
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R
Molecular Biology and Virology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
Hunter
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T
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D016762:Genes, fos; D006801:Humans; D007668:Kidney; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000737:chemistry / Q000302:isolation & purification; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494193:ELK4 protein, human; D010748:Phosphopeptides; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D050808:ets-Domain Protein Elk-4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases