Novel aspects of glypican glycobiology

Abstract

Mutations in glypican genes cause dysmorphic and overgrowth syndromes in men and mice, abnormal development in flies and worms, and defective gastrulation in zebrafish and ascidians. All glypican core proteins share a characteristic pattern of 14 conserved cysteine residues. Upstream from the C-terminal membrane anchorage are 3-4 heparan sulfate attachment sites. Cysteines in glypican-1 can become nitrosylated by nitric oxide in a copper-dependent reaction. When glypican-1 is exposed to ascorbate, nitric oxide is released and participates in deaminative cleavage of heparan sulfate at sites where the glucosamines have a free amino group. This process takes place while glypican-1 recycles via a nonclassical, caveolin-1-associated route. Glypicans are involved in growth factor signalling and transport, e.g. of polyamines. Cargo can be unloaded from heparan sulfate by nitric oxide-dependent degradation. How glypican and its degradation products and the cargo exit from the recycling route is an enigma.

Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes

“…Alternatively, GPC1 may act through a distinct, yet-to-be-described, signaling pathway. While cellular uptake and even nuclear localization of GPC1 have been described (32,33), NHA cells were infected with control or GPC1 adenovirus for 48 h at different doses as indicated. Both cell-associated and shed HSPGs were isolated, and immunoblotting analysis was performed using the anti-pan-HSPG antibody 3G10.…”

Novel aspects of vitamin C: how important is glypican-1 recycling?

“…Ascorbate also affects the turn-over of glypican-1, a complex protein conjugated with both lipid and glycosaminoglycan and involved in cell growth and differentiation; for review, see [32]. Glypican-1 is a glycosylphosphatidylinositol (GPI)-anchored, lipid raft-associated heparan sulfate proteoglycan that is internalized via a caveolinassociated route and recycles via endosomes and the Golgi back to the cell surface (Box 1).…”

Organ-specific Heparan Sulfate Structural Phenotypes

“…Treatment of HS with recombinant 3-O-sulfotransferase created tetrasaccharides containing an IdoA2S-GlcNS3SϮ6S unit (25)(26)(27). Free amino-containing disaccharides in glypican-1 HS chains have been found to be susceptible to nitric oxide (NO)-mediated cleavage as part of the regulation of polyamine uptake (28,29).…”