Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail.
Hepatocyte growth factor/scatter factor (HGF) exerts several functions in physiological and pathological processes, among them the induction of epithelial cell scattering and motility. Its pivotal role in angiogenesis, tumor progression, and metastasis is evident; however, the underlying molecular mechanisms are still poorly understood. Here, we demonstrate that HGF induces scattering of epithelial cells by upregulating the expression of Snail, a transcriptional repressor involved in epithelial-mesenchymal transition (EMT). Snail is required for HGF-induced cell scattering, since shRNA-mediated ablation of Snail expression prevents this process. HGF-induced upregulation of Snail transcription involves activation of the mitogen-activated protein kinase (MAPK) pathway and requires the activity of early growth response factor-1 (Egr-1). Upon induction by Egr-1, Snail represses the expression of E-cadherin and claudin-3 genes. It also binds to the Egr-1 promoter and represses Egr-1 transcription, thereby establishing a negative regulatory feedback loop. These findings indicate that Snail upregulation by HGF is mediated via the MAPK/Egr-1 signaling pathway and that both Snail and Egr-1 play a critical role in HGF-induced cell scattering, migration, and invasion.
Grotegut
Stefan
S
Department of Clinical-Biological Sciences, Institute of Biochemistry and Genetics, Center of Biomedicine, University of Basel, Basel, Switzerland.
von Schweinitz
Dietrich
D
Christofori
Gerhard
G
Lehembre
François
F
D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology
D015820:Cadherins; D051766:Early Growth Response Protein 1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3