Type I collagen promotes epithelial-mesenchymal transition through ILK-dependent activation of NF-kappaB and LEF-1.
Collagen I has been shown to promote epithelial-mesenchymal transition (EMT), a critical process of embryonic development and disease progression. However, little is known about the signaling mechanisms by which collagen I induces this cellular transformation. Here we show that collagen I causes ILK-dependent phosphorylation of IkappaB and subsequent nuclear translocation of active NF-kappaB, which in turn promotes increased expression of the Snail and LEF-1 transcription factors. ILK also causes inhibitory phosphorylation of GSK-3beta, a kinase that prevents functional activation of both Snail and LEF-1. These transcription factors alter expression of epithelial and mesenchymal markers to initiate EMT and stimulate cell migration. These data provide a foundation for understanding the mechanisms by which collagen I stimulates EMT and identify potential therapeutic targets for suppressing this transition in pathological conditions.
Medici
Damian
D
Division of Matrix Biology, Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. dmedici@bidmc.harvard.edu
Nawshad
Ali
A
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D024042:Collagen Type I / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D000099200:Scaffold Protein ILK
D024042:Collagen Type I; D051821:Lymphoid Enhancer-Binding Factor 1; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099200:Scaffold Protein ILK