title: Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating Hedgehog signaling.
abstract: Glypican-5 (GPC5) is one of the six members of the glypican family. It has been previously reported that GPC5 stimulates the proliferation of rhabdomyosarcoma cells. In this study, we show that this stimulatory activity of GPC5 is a result of its ability to promote Hedgehog (Hh) signaling. We have previously shown that GPC3, another member of the glypican family, inhibits Hh signaling by competing with Patched 1 (Ptc1) for Hh binding. Furthermore, we showed that GPC3 binds to Hh through its core protein but not to Ptc1. In this paper, we demonstrate that GPC5 increases the binding of Sonic Hh to Ptc1. We also show that GPC5 binds to both Hh and Ptc1 through its glycosaminoglycan chains and that, unlike GPC3, GPC5 localizes to the primary cilia. Interestingly, we found that the heparan sulfate chains of GPC5 display a significantly higher degree of sulfation than those of GPC3. Based on these results, we propose that GPC5 stimulates Hh signaling by facilitating/stabilizing the interaction between Hh and Ptc1.
authors.affiliation: Division of Molecular and Cell Biology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fuchuan
authors.initials: F
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Shi
authors.forename: Mariana
authors.initials: M
authors.lastname: Capurro
authors.forename: Jorge
authors.initials: J
authors.lastname: Filmus
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053673:Glypicans / Q000378:metabolism / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C105937:GPC3 protein, human; C106228:GPC5 protein, human; D053673:Glypicans; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human