Fine-tuning of cell signaling by glypicans

Abstract

Signaling peptides of the extracellular environment regulate cell biological processes underlying embryonic development, tissue homeostasis, and pathophysiology. The heparan sulphate proteoglycans, glypicans, have evolved as essential modulators of key regulatory proteins such as Wnt, Bmp, Fgf, and Shh. By acting on signal spreading and receptor activation, glypicans can control signal read-out and fate in targeted cells. Genetic and embryological studies have highlighted that glypicans act in a temporal and spatially regulated manner to modulate distinct cellular events. However, alterations of glypican function underlie human congenital malformations and cancer. Recent reports are starting to reveal their mechanism of action and how they can ensure tight modulation of cell signaling.

Cell polarity

“…75 Kny is a member of the glypican family of heparan sulfate proteoglycans that interact with multiple signaling ligands, and therefore, the phenotype might result from pleiotropic effects on signaling pathways activated by other heparan sulfate binding factors. 79 However, in the context of convergent extension, Kny does not appear to regulate Hedgehog, fibroblast growth factor or bone morphogenetic protein signaling. 75,76 Glypican-4, a homolog of Knypek, has also been shown to act in conjunction with Wnt11 and Dishevelled to regulate convergent extension cell movements in Xenopus via non-canonical Wnt signaling.…”

Signalling Mechanisms Underlying Congenital Malformation: The Gatekeepers, Glypicans

“…Gpcs are evolutionarily conserved proteins found in organisms as distinct as nematodes, fruit flies and mammals (De Cat and David, 2001;Fico et al, 2007;. The human and mouse genome contain six Gpc family members, Gpc-1 to Gpc-6 in humans and gpc-1 to gpc-6 in mice (De Cat and David, 2001;Fico et al, 2007;) whereas five gpc-like genes have been identified in zebrafish Topczewski et al, 2001), two in Drosophila (dally and dally-like; Baeg et al, 2001;Nakato et al, 1995) and two in C. elegans (gpn-1 and lon-2; Gumienny et al, 2007;Hudson et al, 2006).…”

“…The amino acid sequences of mammalian Gpc vary from being 17% to 63% identical. However, sequence relationships and exon organizations suggest that mammalian gpcs consist of two distinct subfamilies (De Cat and David, 2001;Fico et al, 2007;. The first subfamily includes gpc-1, -2, -4 and -6 genes with amino acid sequence homology ranging from 40-60% and composed of nine exons.…”

“…Of note, gpc-6 maps near to gpc-5 on mouse chromosome 14 and on human chromosome 13. Gpc-4, which is most homologous to gpc-6 maps to chromosome Xq26 near to gpc-3, which is highly related to gpc-5 (De Cat and David, 2001;Fico et al, 2007;. Therefore, members of the different subfamilies are inclined to cluster on the same chromosome.…”

“…Being mostly extracellular, Gpcs are involved in the regulation of various signalling pathways triggered by secreted peptides including that of Wnt, Fgf, Hh, bone morphogenic protein (Bmp), insulin-like growth factor and hepatocyte growth factor (Fico et al, 2007;.…”