Chondroitin sulfate glycosaminoglycans function as extra/pericellular ligands for cell surface receptors

Chondroitin sulfate (CS) chains, a class of sulfated glycosaminoglycan (GAG) polysaccharides, are ubiquitously distributed in extra/pericellular matrices that establish microenvironmental niches to support a multitude of cellular events. Such wide-ranging functions of CS chains are attributable not only to their sulfation pattern-dependent structural divergence, but also to their multiple modes of action. Although it has long been accepted that CS chains act as passive structural scaffolds that often behave as co-receptors and/or reservoirs for various humoral factors, the discovery of cell surface receptor molecules for distinct CS chains has offered insights into a novel mode of CS function as dynamic extra/pericellular signaling ligands. A recent report by Gong et al. (Identification of PTPRσ-interacting proteins by proximity-labeling assay. J. Biochem. 2021; 169:187-194) also strongly reinforced the physiological importance of CS receptor-mediated signaling pathways. In this commentary, we briefly introduce the functional aspects of CS chains as extra/pericellular signaling molecules.