Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements.
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.
De Cat
Bart
B
Department of Human Genetics, University of Leuven and Flanders Institute for Biotechnology, B-3000 Leuven, Belgium.
Muyldermans
Sin-Ya
SY
Coomans
Christien
C
Degeest
Gisèle
G
Vanderschueren
Bernadette
B
Creemers
John
J
Biemar
Frédéric
F
Peers
Bernard
B
David
Guido
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016466:CHO Cells; D019556:COS Cells; D002465:Cell Movement / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D006224:Cricetinae; D004285:Dogs; D005775:Gastrula / Q000166:cytology / Q000201:enzymology*; D040181:Genetic Diseases, X-Linked / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D015027:Zebrafish; D029961:Zebrafish Proteins
D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D043484:Proprotein Convertases; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D029961:Zebrafish Proteins; C085389:WNT5A protein, human; C094522:wnt8b protein, zebrafish