title: Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling.
abstract: Endoglin is an accessory component of the TGF-β-binding receptor complex that differentially modulates TGF-β and BMP responses. The existence of two splice variants L- and S-endoglin which differ in their cytoplasmic domain has already been shown in human and mice. Endoglin is located on the cell surfaces of cultured hepatic stellate cells and transdifferentiated myofibroblasts suggesting that this receptor might be associated with the profibrogenic attributes of these liver cell subpopulations. We now show that endoglin expression is increased in transdifferentiating hepatic stellate cells and in two models of liver fibrosis (i.e. bile duct ligation and carbon tetrachloride model) and further detectable in cultured portal fibroblasts representing another important fibrogenic cell type but not in hepatocytes. In respect to TGF-β1-signalling, we demonstrate that endoglin interacts with and is phosphorylated by TβRII. In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor. We further identified a novel rat splice variant that is structurally and functionally different from that identified in human and mouse. Transient overexpression of endoglin resulted in a strong increase of TGF-β1-driven Smad1/5 phosphorylation and α-smooth muscle actin expression in a hepatic stellate cell line. In supernatants of respective cultures, we could detect the ectodomain of endoglin suggesting that shedding is a further key process involved in the regulation of this surface receptor.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany. smeurer@ukaachen.de
authors.forename: Steffen K
authors.initials: SK
authors.lastname: Meurer
authors.forename: Lidia
authors.initials: L
authors.lastname: Tihaa
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000071063:Endoglin; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; C501740:Eng protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1