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Published 10 November 2003. doi:10.1083/jcb.200302152
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© The Rockefeller University Press, 0021-9525/2003/11/625 $8.00
The Journal of Cell Biology, Volume 163, Number 3, 625-635

Article

Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements



Bart De Cat1, Sin-Ya Muyldermans1, Christien Coomans1, Gisèle Degeest1, Bernadette Vanderschueren1, John Creemers2, Frédéric Biemar3, Bernard Peers3 and Guido David1

1 Laboratory for Glycobiology and Developmental Genetics, Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium
2 Laboratory for Molecular Oncology, Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium
3 Laboratoire de Biologie Moléculaire et de Génie Génétique, Université de Liège, B-4000 Liège, Belgium

Address correspondence to Guido David, Center for Human Genetics, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-345863. Fax: 32-16-347166. email: guido.david{at}med.kuleuven.ac.be

Glypican (GPC)-3 inhibits cell proliferation and regulates cell survival during development. This action is demonstrated by GPC3 loss-of-function mutations in humans and mice. Here, we show that the GPC3 core protein is processed by a furinlike convertase. This processing is essential for GPC3 modulating Wnt signaling and cell survival in vitro and for supporting embryonic cell movements in zebrafish. The processed GPC3 core protein is necessary and sufficient for the cell-specific induction of apoptosis, but in vitro effects on canonical and noncanonical Wnt signaling additionally require substitution of the core protein with heparan sulfate. Wnt 5A physically associates only with processed GPC3, and only a form of GPC3 that can be processed by a convertase is able to rescue epiboly and convergence/extension movements in GPC3 morphant embryos. Our data imply that the Simpson–Golabi–Behmel syndrome may in part result from a loss of GPC3 controls on Wnt signaling, and suggest that this function requires the cooperation of both the protein and the heparan sulfate moieties of the proteoglycan.

Key Words: glypican; Wnt; furin; epiboly; apoptosis

Abbreviations used in this paper: BFA, brefeldin A; CRD, cysteine-rich domain; GPC, glypican; GPI, glycosylphosphatidylinositol; hpf, hours post fertilization; HS, heparan sulfate; HSPG, heparan sulfate proteoglycan; JNK, c-Jun NH2-terminal protein kinase; PC, proprotein convertase; SGBS, Simpson-Golabi-Behmel syndrome.


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