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

TitleProcessing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements.
Publication TypeJournal Article
Year of Publication2003
AuthorsDe Cat, B., S-Y. Muyldermans, C. Coomans, G. Degeest, B. Vanderschueren, J. Creemers, F. Biemar, B. Peers, and G. David
JournalJ Cell Biol
Volume163
Issue3
Pagination625-35
Date Published2003 Nov 10
ISSN0021-9525
KeywordsAnimals, Apoptosis, Cell Movement, Cell Survival, CHO Cells, COS Cells, Cricetinae, Dogs, Gastrula, Genetic Diseases, X-Linked, Glypicans, Heparan Sulfate Proteoglycans, Heparitin Sulfate, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinases, Proprotein Convertases, Protein Structure, Tertiary, Proto-Oncogene Proteins, Wnt Proteins, Zebrafish, Zebrafish Proteins
Abstract

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.

DOI10.1083/jcb.200302152
Alternate JournalJ. Cell Biol.
PubMed ID14610063
PubMed Central IDPMC2173654