Glypican-3 binds to frizzled and plays a direct role in the stimulation of canonical Wnt signaling

Abstract

Glypican-3 (GPC3) is a proteoglycan that is bound to the cell surface. It is expressed by most hepatocellular carcinomas (HCCs) but not by normal hepatocytes. GPC3 stimulates HCC growth by promoting canonical Wnt signaling. Because glypicans interact with Wnts, it has been proposed that these proteoglycans stimulate signaling by increasing the amount of Wnt at the cell membrane, thus facilitating the interaction of this growth factor with its signaling receptor, Frizzled. However, in this study, we demonstrate that GPC3 plays a more direct role in the stimulation of Wnt signaling. Specifically, we show that, in addition to interacting with Wnt, GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3, indicating that this glypican stimulates the formation of signaling complexes between Wnt and Frizzled. Consistent with this, we show that the binding of Wnt at the cell membrane triggers the endocytosis of a complex that includes Wnt, Frizzled and GPC3. Additional support for our model is provided by the finding that glypican-6 (GPC6) inhibits canonical Wnt signaling, despite the fact that it binds to Wnt at the cell membrane.

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

“…In hepatocellular carcinoma cells, this oncofetal antigen binds to Frizzled, thereby promoting WNT signaling, which stimulates growth. 78 Our data suggest that the opposite might be true in preeclampsia. The very low-density lipid receptor (VLDLE) was also in this category.…”

Processing by Convertases Is Required for Glypican-3-induced Inhibition of Hedgehog Signaling

“…CM, conditioned medium. mechanism has been proposed to explain GPC3-induced stimulation of Wnt signaling (27). We have recently shown that GPC3 plays a direct role in the activation of Wnt signaling by binding to both Wnt and its receptor Frizzled (Fz) and by stimulating the formation of signaling complexes (27).…”

“…mechanism has been proposed to explain GPC3-induced stimulation of Wnt signaling (27). We have recently shown that GPC3 plays a direct role in the activation of Wnt signaling by binding to both Wnt and its receptor Frizzled (Fz) and by stimulating the formation of signaling complexes (27). Because the convertase-resistant GPC3 is as potent as wild-type GPC3 in the stimulation of Wnt signaling (23), our data suggest that the structural changes generated by the lack of convertase cleavage do not alter GPC3-Wnt and GPC3-Fz binding interactions.…”

Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma

“…Immunohistochemical analysis indicated that downregulation of GPC-3 with miRNA significantly (p < 0.01) decreases expression of β-catenin, p-GSK3β, and cyclin D1. β-catenin and GSK3β are known to play an important role in regulating metabolism, transcription, embryonic development, and other processes and to also play a key role in the Wnt/β-catenin-induced phosphorylation of GSK3β, which results in the dissolution of the complex responsible for β-catenin degradation (62,63). A therapeutic intervention targeting GPC-3 is a promising approach for the clinical management of HCC.…”