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The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer

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Review

The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer

Aarti Kolluri et al. Front Oncol.

Abstract

Glypican-3 (GPC3) is a cell-surface glycoprotein consisting of heparan sulfate glycosaminoglycan chains and an inner protein core. It has important functions in cellular signaling including cell growth, embryogenesis, and differentiation. GPC3 has been linked to hepatocellular carcinoma and a few other cancers, however, the mechanistic role of GPC3 in cancer development remains elusive. Recent breakthroughs including the structural modeling of GPC3 and GPC3-Wnt complexes represent important steps toward deciphering the molecular mechanism of action for GPC3 and how it may regulate cancer signaling and tumor growth. A full understanding of the molecular basis of GPC3-mediated signaling requires elucidation of the dynamics of partner receptors, transducer complexes, and downstream players. Herein, we summarize current insights into the role of GPC3 in regulating cancer development through Wnt and other signaling pathways, including YAP and hedgehog cascades. We also highlight the growing body of work which underlies deciphering how GPC3 is a key player in liver oncogenesis.

Keywords: Wnt signaling; YAP signaling; antibody therapy; heparan sulfate proteoglycan; liver cancer.

Figures

Figure 1
Figure 1
A model for the role of GPC3 in regulating Wnt in liver cancer. (A) When no GPC3 is present, Wnt can independently activate FZD without GPC3 co-ordination. In the absence of GPC3, there is a baseline level of Wnt/β-catenin activation in normal liver cells. (B) When GPC3 is upregulated in malignant liver cells (HCC), GPC3 serves as a Wnt co-receptor to attract Wnt to the cell surface via a hydrophobic groove in the N-lobe of GPC3 containing F41 and surrounding residues. (C) When FZD is locally concentrated and GPC3 is high in HCC cells, the Wnt/GPC3/FZD complex is formed, and Wnt signaling is amplified.
Figure 2
Figure 2
The model for the role of GPC3 in regulating Hedgehog signaling. (A) In the presence of Hh ligand, PTCH promotes surface localization and activation of SMO. SMO transduces the Hh signal within the cytoplasm. Protein kinases phosphorylate GLI proteins, leading to an NH2-terminal truncated form, which travels to the nucleus and activates Hh signaling. (B) GPC3 competes with PTCH for Hh binding which results in inhibition of hedgehog signaling. GPC3 binds both Shh and Ihh, resulting in the endocytosis and lysosomal degradation of the GPC3/Hh complex in the presence of LRP1.

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