Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth.
Glypicans are a family of heparan sulfate proteoglycans that are bound to the cell surface by a lipid anchor. Six members of this family have been identified in mammals (GPC1-GPC6). Glypicans act as regulators of the activity of various cytokines, including Wnts, Hedgehogs, and bone morphogenetic proteins. It has been reported that processing by a convertase is required for GPC3 activity during convergent extension in zebrafish embryos, for GPC3-induced regulation of Wnt signaling, and for the binding of GPC3 to Wnt5a. In our laboratory, we have recently demonstrated that GPC3 promotes the growth of hepatocellular carcinomas (HCCs) by stimulating canonical Wnt signaling. Because there is increasing evidence indicating that the structural requirements for GPC3 activity are cell type specific, we decided to investigate whether GPC3 needs to be processed by convertases to stimulate cell proliferation and Wnt signaling in HCC cells. We report here that a mutant GPC3 that cannot be processed by convertases is still able to play its stimulatory role in Wnt activity and HCC growth.
Capurro
Mariana I
MI
Division of Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
Shi
Wen
W
Sandal
Shaifali
S
Filmus
Jorge
J
D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
D017077:Culture Media, Conditioned; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D008156:Luciferases; D016282:Aspartic Acid Endopeptidases