HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1

In this study, we show that the ETS transcription factor ER81 directly bind s to and activates the promoter of the matrix metalloproteinase gene, MMP-1 . Further, the oncoprotein HER2/Neu synergizes with ER81 to stimulate MMP-1 transcription, The activation of ER81 by HER2/Neu is mediated by MAP kinas es, which phosphorylate ER81 in its N-terminal activation domain. Four resp ective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be furth er diminished by abolishment of phosphorylation at two non-MAP kinase sites , Altogether, our results reveal mechanisms of how phosphorylation of ER81 regulates the expression of target genes such as MMP-1, which may be import ant for many physiological processes from embryogenesis to adulthood as wel l as for tumor metastasis.