title: Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells.
abstract: Epithelial-mesenchymal transition (EMT) plays an important role in organ fibrosis, including that of the kidney. Loss of E-cadherin expression is a hallmark of EMT; however, whether the loss of E-cadherin is a consequence or a cause of EMT remains unknown, especially in the renal system. In this study, we show that transforming growth factor (TGF)-beta1-induced EMT in renal tubular epithelial cells is dependent on proteolysis. Matrix metalloproteinase-mediated E-cadherin disruption led directly to tubular epithelial cell EMT via Slug. TGF-beta1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of beta-catenin, the transcriptional induction of Slug, and the repression of E-cadherin transcription in tubular epithelial cells. These findings reveal a direct role for E-cadherin and for matrix metalloproteinases in causing EMT downstream of TGF-beta1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease.
authors: Centre for Transplantation and Renal Research, the University of Sydney at Westmead Millennium Institute, Westmead, NSW 2145 Australia. guoping_zheng@wmi.usyd.edu.au
authors: Guoping
authors: G
authors: Zheng
authors: James Guy
authors: JG
authors: Lyons
authors: Thian Kui
authors: TK
authors: Tan
authors: Yiping
authors: Y
authors: Wang
authors: Tzu-Ting
authors: TT
authors: Hsu
authors: Danqing
authors: D
authors: Min
authors: Lena
authors: L
authors: Succar
authors: Gopala K
authors: GK
authors: Rangan
authors: Min
authors: M
authors: Hu
authors: Beric R
authors: BR
authors: Henderson
authors: Stephen I
authors: SI
authors: Alexander
authors: David C H
authors: DC
authors: Harris
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D054337:Cell Dedifferentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004848:Epithelium / Q000473:pathology*; D005355:Fibrosis; D007684:Kidney Tubules / Q000473:pathology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008648:Mesoderm / Q000473:pathology*; D051381:Rats; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9