Role of glypican-1 in regulating multiple cellular signaling pathways

Abstract

Glypican-1 (GPC1) is one of the six glypican family members in humans. It is composed of a core protein with three heparan sulfate chains and attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. GPC1 modulates various signaling pathways including fibroblast growth factors (FGF), vascular endothelial growth factor-A (VEGF-A), transforming growth factor-β (TGF-β), Wnt, Hedgehog (Hh), and bone morphogenic protein (BMP) through specific interactions with pathway ligands and receptors. The impact of these interactions on signaling pathways, activating or inhibitory, is dependent upon specific GPC1 domain interaction with pathway components, as well as cell surface context. In this review, we summarize the current understanding of the structure of GPC1, as well as its role in regulating multiple signaling pathways. We focus on the functions of GPC1 in cancer cells and how new insights into these signaling processes can inform its translational potential as a therapeutic target in cancer.

Keywords: cancer; glypican-1; signaling pathways; therapeutic target.

Figure 1.

GPC1 structure and the regulatory roles of GPC1 in multiple-signaling pathways. A: schematic of human GPC1 core protein linked to the cell membrane by its GPI anchor. The highly conserved Cys residues are indicated in yellow. The disulfide bonds formed by the Cys residues are indicated by purple lines. Two N-linked glycans indicated by black are at positions Asn-79 and Asn-116. Three HS chains are located at Ser-486, Ser-488, and Ser-490. B: overview of the GPC1ΔC crystal structure. Seven disulfide bonds are highlighted by red solid lines. The sequences before and after the predicted furin cleavage site are indicated by cyan and light pink, respectively. Cys residues before and after furin cleavage site are highlighted in blue and magenta, respectively. C: GPC1 modulates various signaling pathways in cancer progression and other physiological processes. GPC1 can interact with both heparin-binding growth factors (FGF and VEGF-A) and their receptors to stabilize their assembly and enhance MARK or PI3K/Akt signaling. GPC1 also binds TGF-β and its receptors to promote SMAD signaling. However, GPC1 plays a negative role in BMP cascades by competing with BMP receptors to interact with BMPs. GPC1 might serve as a Wnt coreceptor to activate Wnt signaling. BMP, bone morphogenic protein; FGF, fibroblast growth factor; FGFR, fibroblast growth factors receptor; GPC1, glypican-1; GPI, glycosyl-phosphatidylinositol; HS, heparan sulphate; TGF-β, transforming growth factor-β; VEGF-A, vascular endothelial growth factor-A.

Figure 2.

The potential role of GPC1 in regulating Wnt signaling pathway. A: at baseline without R-spondins (RSPOs), transmembrane E3 ubiquitin ligases (ZNRF3 or RNF43) reduce cell surface levels of Wnt receptors Frizzled (FZD) by direct ubiquitination, leading to limited Wnt signaling. B: as GPC3, GPC1 might serve as a Wnt coreceptor by directly binding to Wnt via HS chains and/or its core protein to potentiate downstream signaling. C and D: in addition, GPC1 might act as a RSPOs coreceptor to present RSPOs via HS chains in the absence or presence of LGRs. With LGRs, RSPO3 can bind simultaneously to LGRs and GPC1, and together present the RSPO3 to ZNRF3/RNF43, leading to the internalization and degradation of ZNRF3/RNF43. Membrane clearance of ZNRF3/RNF43 results in increased number of FZD at the cell membrane with the consequent enhanced Wnt cascades. Without LGRs, RSPO3 is presented by GPC1 alone to sufficiently induce Wnt signaling potentiating through a similar mechanism. GPC1, glypican-1; HS, heparan sulphate; LGRs, leucine-rich repeat-containing G-protein coupled receptors.

Figure 3.

GPC1 seems to have dual function; GPC1 can augment or attenuate Hedgehog (Hh) signaling. A: in the absence of Hh ligands, Patched suppresses the activity of Smoothened (Smo), thereby inhibiting the downstream signaling. B: when Hh binds to Patched, the inhibition on Smo is released and the following Hh signaling cascade will be activated. C: in cholangiocytes, GPC1 is proposed to function as a negative modulator, probably by binding to Hh but does not interact with Patched, leading to reduced amount of Hh available for binding to Patched and ultimately decreased Hh signaling with attenuated expression level of target genes (gli2a, ptch1, foxl1, znf697, ccnd1). D: GPC1 acts as a positive regulator of Shh in commissural axons guidance. GPC1 interacts with both Shh and Patched in a way that requires the HS chains and core protein to facilitate Hh-Patched interaction, resulting in increased downstream Hh signaling. GPC1, glypican-1; Hhip, Hedgehog-interacting protein; HS, heparan sulphate; shh, sonic Hh.