title: LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex.
abstract: Glypican-3 (GPC3) is a heparan sulfate (HS) proteoglycan that is bound to the cell membrane through a glycosylphosphatidylinositol link. This glypican regulates embryonic growth by inhibiting the hedgehog (Hh) signaling pathway. GPC3 binds Hh and competes with Patched (Ptc), the Hh receptor, for Hh binding. The interaction of Hh with GPC3 triggers the endocytosis and degradation of the GPC3-Hh complex with the consequent reduction of Hh available for binding to Ptc. Currently, the molecular mechanisms by which the GPC3-Hh complex is internalized remains unknown. Here we show that the low-density-lipoprotein receptor-related protein-1 (LRP1) mediates the Hh-induced endocytosis of the GPC3-Hh complex, and that this endocytosis is necessary for the Hh-inhibitory activity of GPC3. Furthermore, we demonstrate that GPC3 binds through its HS chains to LRP1, and that this interaction causes the removal of GPC3 from the lipid rafts domains.
authors.affiliation: Division of Molecular and Cell Biology, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mariana I
authors.initials: MI
authors.lastname: Capurro
authors.forename: Wen
authors.initials: W
authors.lastname: Shi
authors.forename: Jorge
authors.initials: J
authors.lastname: Filmus
mesh_terms: D000818:Animals; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D015398:Signal Transduction; D014162:Transfection
chemical_list: D002966:Clathrin; C105937:GPC3 protein, human; D053673:Glypicans; D053823:Hedgehog Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1