BIOCHEMISTRY Coactivator Interprets MAP Kinase Signals

Signaling pathways mediated by members of the mitogen-activated protein kinase (MAPK) family have similar biochemical properties and yet are able to regulate very different biological processes. In general, the MAP kinases known as ERKs control cell proliferation, whereas the JNK and p38 family members respond to cell stress. Yang and Sharrocks provide a molecular explanation that appears to account, at least in part, for the distinct effects of these similar kinases. The key is differential responses of a protein known as PIASx (protein inhibitor of activated STAT x), which has ubiquitin E3 ligase activity and functions as a transcriptional coactivator. When the ERK pathway is activated, PIASx helps activate the transcription factor Elk-1 by promoting removal of a SUMO molecule (a small protein related to ubiquitin) and concomitant release of HDAC-2 (histone deacetylase 2), an enzyme that suppresses transcriptional activity of Elk-1. Yang and Sharrocks show that activation of p38 uses the same cellular machinery to inhibit Elk-1 dependent transcription. Depletion of PIASx in cultured cells by siRNA enhanced the response of Elk-1 target genes to activation of the p38 pathway, and this effect appeared to depend on direct phosphorylation of PIASx by p38. Chromatin immunoprecipitation experiments showed that somehow this phosphorylated PIASx helped retain sumoylation of Elk-1 and association of HDAC-2 with target genes--the opposite of its effects when stimulated by the ERK pathway. Thus, the authors propose that PIASx may serve to integrate signals from opposing MAP kinase pathways to provide a proper graded response of target genes.

S.-H. Yang, A. D. Sharrocks, PIASx differentially regulates the amplitudes of transcriptional responses following activation of the ERK and p38 MAPK Pathways. Mol. Cell 22, 477-487 (2006). [PubMed]