Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding.
Loss-of-function mutations in glypican-3 (GPC3), one of the six mammalian glypicans, causes the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and GPC3 null mice display developmental overgrowth. Because the Hedgehog signaling pathway positively regulates body size, we hypothesized that GPC3 acts as an inhibitor of Hedgehog activity during development. Here, we show that GPC3 null embryos display increased Hedgehog signaling and that GPC3 inhibits Hedgehog activity in cultured mouse embryonic fibroblasts. In addition, we report that GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding. Furthermore, GPC3 induces Hedgehog endocytosis and degradation. Surprisingly, the heparan sulfate chains of GPC3 are not required for its interaction with Hedgehog. We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development and that the overgrowth observed in SGBS patients is, at least in part, the consequence of hyperactivation of the Hedgehog signaling pathway.
Capurro
Mariana I
MI
Division of Molecular and Cell Biology, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N3M5, Canada.
Xu
Ping
P
Shi
Wen
W
Li
Fuchuan
F
Jia
Angela
A
Filmus
Jorge
J
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004705:Endocytosis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D053673:Glypicans / Q000172:deficiency / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000072079:Patched Receptors; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
D053673:Glypicans; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface