title: Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic human liver.
abstract: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell-collagen interactions in chronic liver injury.
authors.affiliation: Centenary Institute and the A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital and the Sydney Medical School, University of Sydney, New South Wales, Australia.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Song
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Shackel
authors.forename: Xin M
authors.initials: XM
authors.lastname: Wang
authors.forename: Katerina
authors.initials: K
authors.lastname: Ajami
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gorrell
mesh_terms: D000293:Adolescent; D000328:Adult; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D000070819:Discoidin Domain Receptor 1; D005260:Female; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases