Roles of glycosaminoglycans as regulators of ligand/receptor complexes

Abstract

Glycosaminoglycans (GAGs) play a widespread role in embryonic development, as deletion of enzymes that contribute to GAG synthesis lead to deficiencies in cell migration and tissue modelling. Despite the biochemical and structural characterization of individual protein/GAG interactions, there is no concept available that links the molecular mechanisms of GAG/protein engagements to tissue development. Here, we focus on the role of GAG polymers in mediating interactions between cell surface receptors and their ligands. We categorize several switches that lead to ligand activation, inhibition, selection and addition, based on recent structural studies of select receptor/ligand complexes. Based on these principles, we propose that individual GAG polymers may affect several receptor pathways in parallel, orchestrating a cellular response to an environmental cue. We believe that it is worthwhile to study the role of GAGs as molecular switches, as this may lead to novel drug candidates to target processes such as angiogenesis, neuroregeneration and tumour metastasis.

Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of Their Biological Functions

“…As example of a target-protein we selected fibroblast growth factor 2 (FGF-2 or basic fibroblast growth factor). Like other FGF family members, FGF-2 is involved in a large number of biological processes in a GAG cofactor-assisted manner [ 16 , 17 ], and a rising amount of evidence has shown that CSs participate and modulate its binding to its FGFR receptor [ 18 ].…”

Migratory Activities and Stemness Properties of Rodlet Cells

“…They have multiple structural and mechanical roles. GAG polymer acts as an activator that facilitates interaction between receptor/ligand complexes and triggers cell signaling (Smock & Meijers, 2018). Enzymatic GAG depolymerization activates CXCL8-induced endothelial downstream signaling that related to changes in endothelial proteins such as Zyxin and Caldesmon which contribute to the cytoskeletal organization, cell adhesion, and cell mobility (Derler et al, 2017).…”

Reelin Counteracts Chondroitin Sulfate Proteoglycan-Mediated Cortical Dendrite Growth Inhibition

“…Because Reelin and CSPGs are both expressed in the extracellular space of the MZ (Nichols and Olson, 2010), it is possible that Reelin and CSPGs interact directly to modulate receptor binding activity (Smock and Meijers, 2018). To first determine whether Reelin-dependent Dab1 phosphorylation occurs in the presence of CSPGs, we examined Dab1 phosphorylation status.…”

“…CSPGs may inhibit neurite growth by acting as an anti-adhesive substrate (Emerling and Lander, 1996), but specific signaling events have also been demonstrated. For example, subsets of CSPGs are known to bind and augment the signaling of other compounds in the nECM (Smock and Meijers, 2018). In addition, some CSPGs have been shown to directly bind and activate receptors such as receptor tyrosine phosphatase s (RPTPs ) and leukocyte common antigen-related phosphatase (LAR), which are known to functionally inhibit axonal regeneration (Fisher et al, 2011;Lang et al, 2015).…”