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 binds 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 kinases, which phosphorylate ER81 in its N-terminal activation domain. Four respective phosphorylation sites have been identified. Blocking phosphorylation at these sites decreases ER81 transcriptional activity, which can be further 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 important for many physiological processes from embryogenesis to adulthood as well as for tumor metastasis.
Bosc
D G
DG
Department of Biochemistry and Molecular Biology, Guggenheim Building 1501A, Mayo Clinic and Mayo Graduate School, 200 First Street SW, Rochester, MN 55905, USA.
Goueli
B S
BS
Janknecht
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D008156:Luciferases; D020781:Matrix Metalloproteinase 1; D020928:Mitogen-Activated Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases