Novel aspects of glypican glycobiology

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.Received 27 November 2003; received after revision 8 January 2004; accepted 13 January 2004     

Proteoglycans of basement membranes

Proteoglycans carrying either heparan sulfate and/or chondroitin sulfate side chains are typical constituents of basement membranes. The most prominent proteoglycan (perlecan) consists of a 400–500 kDa core protein and three heparan sulfate chains. Electron microscopy and cDNA sequencing show a complex and elongated domain structure for the core protein which in part is homologous to that of the laminin A chain. This structure may be varied by alternative splicing and proteolysis. Integration into basement membranes probably occurs by heparan sulfate binding to laminin and collagen IV, core protein binding to nidogen and by limited self assembly. The proteoglycan is in addition a cell-adhesive protein which is recognized by 1 integrins. Several more proteoglycans with smaller core proteins (10–160 kDa) apparently exist in basement membranes but are less well characterized. Biological functions include control of filtration through basement membranes and binding of growth factors and protease inhibitors.