Activation of ternary complex factor Elk-1 by stress-activated protein kinases.
BACKGROUND
The mammalian response to stress results in the activation of stress-activated protein kinases (also known as cJun N-terminal kinases; SAPKs or JNKs), which are a sub-group of the mitogen-activated protein (MAP) kinase family. The SAPKs are involved in the upregulation of activity of the transcription factor AP-1 by post-translational modification of two of its components, cJun and ATF2. AP-1 activity can also be elevated by increased expression of the Fos protein, a further AP-1 component. Elk-1 (also called p62TCF), a transcription factor involved in the induction of the expression from the c-fos promoter through the promoter's serum response element, is known to be activated as a result of phosphorylation by the MAP kinases ERK1 and ERK2. However, induction of c-fos expression in response to noxious agents takes place in the absence of ERK activation. We therefore investigated whether SAPKs similarly upregulate c-fos expression by phosphorylating Elk-1.


RESULTS
Elk-1 is activated in response to stimuli other than mitogenic signals. Both p46SAPK and p54SAPK interact physically with, and phosphorylate, Elk-1. The capacity of Elk-1 to form a ternary complex with serum response factor in vitro is thereby elevated. In vivo, selective activation of SAPKs stimulates formation of the ternary complex containing Elk-1, serum response factor and the serum response element, and enhances Elk-1-dependent transcription. Expression of the SAPK upstream-activator kinase, MEKK1, induces SAPK activation and c-fos transcription in the absence of ERK activity. Phosphopeptide mapping of Elk-1 phosphorylated with p46SAPK or p54SAPK reveals Ser383, a residue critical for ternary complex formation and transcriptional activation, to be the major phosphorylation site.


CONCLUSIONS
Elk-1 responds to stress-induced, as well as mitogenic, signals by stimulating c-fos transcription through the serum response element. Phosphorylation of Elk-1 by SAPKs and the ensuing expression of Fos protein thus constitutes an additional mechanism by which cells can upregulate AP-1 activity in response to stress.
Max-Planck-Institut für Immunbiologie, Spemann Laboratories, Freiburg, Germany.
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H
Gille
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Strahl
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PE
Shaw
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D026362:Serum Response Factor; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D048056:Mitogen-Activated Protein Kinase 9; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases