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 FGF, VEGF-A, TGF-β, Wnt, Hh, and 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.

Glypican-1 drives unconventional secretion of fibroblast growth factor 2

“…With these observations, while GPC1 is not essential for FGF signaling, our study reveals an intimate relationship between FGF2 and GPC1 in the secretion of FGF2 from cells. Since both FGF2 and GPC1 are key components of tumor progression for a wide range of cancer types ( Akl et al, 2016 ; Pan and Ho, 2021 ), we propose that the prominent function of GPC1 in driving efficient unconventional secretion of FGF2 might play a key role for tumor development such as acute myeloid leukemia ( Traer et al, 2016 ; Javidi-Sharifi et al, 2019 ).…”

APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer

“…These transcriptional pathways reside downstream of cell-surface receptors, many of which are known to be influenced by the activity of Glypicans, a family of proteoglycans that can be cleaved from the cell surface by NOTUM activity [8,10] . For example, Glypicans have been implicated in the regulation of WNT, TGFߚ, IGF, FGF, VEGF, Hh, HGF, and BMP receptor activity, primarily in studies carried out in Drosophila [8,[21][22][23][24][25][26][27][28][29][30][31][32] . In mammals, how each of the six paralogous orthologs of Drosophila Glypicans (mammalian Gpc1-6) influence activity of these receptors and in which context remains poorly understood.…”

“…Glypicans are a family of proteoglycans, comprising two members in drosophila (Dally and Dally-like-protein, Dlp), that have expanded to six paralogous orthologs in mammals (Gpc1-6) [41] . Dally and Dlp have been implicated in the regulation of most known signal transduction pathways, including WNT, TGFβ, IGF, FGF, VEGF, Hh, HGF, and BMP [8,[21][22][23][24][25][26][27][28][29][30][31][32] . Most current models for Glypican function indicate that these proteoglycans, when anchored to the cell surface, act to potentiate receptor-ligand interactions.…”

The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis

“…If so, then the GT47 domain (which sits between the coiled coil and the GT64 domain) may simply contribute to the gap between membrane and GlcNAcT-I/II active site. However, some EXTL3 substrates appear to be closely associated with the membrane; for instance, glypican-1 possesses an HS addition site a mere 40 residues from its GPI anchor 61 . It is hard to explain how EXTL3’s rigid stem would help it to access such a substrate.…”