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 ki nases; SAPKs or JNKs), which are a sub-group of the mitogen-activated protein (MAP) kinase family. The SAPKs are involved in the upregulatio n of activity of the transcription factor AP-1 by post-translational m odification of two of its components, cJun and ATF2. AP-1 activity can also be elevated by increased expression of the Fos protein, a furthe r AP-I component. Elk-1 (also called p62(TCF)), transcription factor i nvolved in the induction of the expression from the c-fos promoter thr ough the promoter's serum response element, is known to be activated a s a result of phosphorylation by the MAP kinases ERK1 and ERK2. Howeve r, induction of c-fos expression in response to noxious agents takes p lace in the absence of ERK activation. We therefore investigated wheth er SAPKs similarly upregulate c-fos expression by phosphorylating Elk- 1. Results: Elk-1 is activated in response to stimuli other than mitog enic signals. Both p46(SAPK) and P54(SAPK) interact physically with, a nd phosphorylate, Elk-1. The capacity of Elk-1 to form a ternary compl ex with serum response factor in vitro is thereby elevated. In vivo, s elective activation of SAPKs stimulates formation of the ternary compl ex containing Elk-1, serum response factor and the serum response elem ent, and enhances Elk-1-dependent transcription. Expression of the SAP K upstream-activator kinase, MEKK1, induces SAPK activation and c-fos transcription in the absence of ERK activity. Phosphopeptide mapping o f Elk-1 phosphorylated with p46(SAPK) or p54(SAPK) reveals Ser383, a r esidue critical for ternary complex formation and transcriptional acti vation, to be the major phosphorylation site. Conclusion: Elk-1 respon ds to stress-induced, as well as mitogenic, signals by stimulating c-f os transcription through the serum response element. Phosphorylation o f Elk-1 by SAPKs and the ensuing expression of Fos protein thus consti tutes an additional mechanism by which cells can upregulate AP-1 activ ity in response to stress.