title: Insulin receptor substrate-1 suppresses transforming growth factor-beta1-mediated epithelial-mesenchymal transition.
abstract: We investigated the regulatory effect of insulin receptor substrate-1 (IRS-1) on transforming growth factor-beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT). TGF-beta1-induced EMT and cell migration in A549 cells are associated with a decrease in IRS-1 tyrosine phosphorylation and protein levels. Tissue microarray analysis of human lung carcinoma shows a correlation between IRS-1 protein levels and E-cadherin protein levels. High IRS-1 levels coexist with high E-cadherin levels, whereas low IRS-1 levels coexist with low E-cadherin levels, implying a possibility that IRS-1 protein levels may be linked with EMT. Surprisingly, overexpression of IRS-1 in A549 cells completely blocked TGF-beta1-induced EMT and cell migration, inhibited TGF-beta1-mediated expression of snail and slug genes, and abolished TGF-beta1-mediated repression of E-cadherin promoter activity. In contrast, IRS-1 knockdown by RNAi increased the expression of snail and slug genes and induced EMT. Inhibition of protein tyrosine phosphatase with sodium vanadate, which greatly increased the levels of tyrosine-phosphorylated IRS-1, suppressed TGF-beta1-induced actin remodeling and cell morphologic changes. These results show for the first time that TGF-beta1 induces EMT through mechanisms involving the modulation of IRS-1 signaling, and that IRS-1 functions as a critical EMT suppressor that suppresses TGF-beta1-induced EMT via inhibition of snail and slug expression.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Liu
authors.forename: Yong-Lian
authors.initials: YL
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Song
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D015820:Cadherins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1