The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

Abstract

This review examines the roles of HS–proteoglycans (HS–PGs) in general, and, in particular, perlecan and syndecan as representative examples and their interactive ligands, which regulate physiological processes and cellular behavior in health and disease. HS–PGs are essential for the functional properties of tissues both in development and in the extracellular matrix (ECM) remodeling that occurs in response to trauma or disease. HS–PGs interact with a biodiverse range of chemokines, chemokine receptors, protease inhibitors, and growth factors in immune regulation, inflammation, ECM stabilization, and tissue protection. Some cell regulatory proteoglycan receptors are dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic stabilization, plasticity, and specificity of interaction, promoting neurotransduction, neurogenesis, and differentiation. Ternary complexes of glypican-1 and Robbo–Slit neuroregulatory proteins direct axonogenesis and neural network formation. Specific neurexin–neuroligin complexes stabilize synaptic interactions and neural activity. Disruption in these interactions leads to neurological deficits in disorders of functional cognitive decline. Interactions with HS–PGs also promote or inhibit tumor development. Thus, HS–PGs have complex and diverse regulatory roles in the physiological processes that regulate cellular behavior and the functional properties of normal and pathological tissues. Specialized HS–PGs, such as the neurexins, pikachurin, and Eyes-shut, provide synaptic stabilization and specificity of neural transduction and also stabilize the axenome primary cilium of phototoreceptors and ribbon synapse interactions with bipolar neurons of retinal neural networks, which are essential in ocular vision. Pikachurin and Eyes–Shut interactions with an α-dystroglycan stabilize the photoreceptor synapse. Novel regulatory roles for HS–PGs controlling cell behavior and tissue function are expected to continue to be uncovered in this fascinating class of proteoglycan.

Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes

“…Structurally, GPC4 consists of a core protein substituted with heparan sulfate chains (HS), all anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage that anchors GPC4 to the cytoplasmic surface of cellular membranes. The functional relevance of GPC4 can be attributed to both its core protein and its HS chains, which affect its interactions with various molecules in terms of selectivity and binding affinities, thereby contributing to the complexity of cellular communication and fine-tuning signaling pathways [43]. The HS display a tremendous structural diversity as a result of a tightly controlled biosynthetic pathway, exhibiting differential regulation in different organs, stages of development, and pathologies, including cancer.…”

Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc

“…The HS side chains of perlecan equip it with an ability to interact with a diverse range of ligands (Table 1 ) of importance in cartilage development and ECM remodeling, in tissue morphogenesis, and in tissue repair responses. 11 , 21 , 22 , 25 , 26 , 27 , 28 , 29 , 30 This establishes perlecan as a PG of some importance in the development and stabilization of IVD tissues equipping IVD cells with cell‐matrix communicative properties that sense perturbations in their biomechanical environment allowing the IVD cell to orchestrate tissue homeostasis and the maintenance of IVD function. 3 , 31 …”

“… Note : Data compiled from references 7 , 12 , 13 , 19 , 20 , 21 , 22 , 23 , 24 . Table adapted from reference 25 with permission. Abbreviations: Ang‐3, angiogenin like protein‐3; BMP, bone morphogenetic protein; CSPG4, melanoma‐associated chondroitin sulfate proteoglycan, or neuron‐glial antigen 2; ECM‐1, ECM protein‐1; FGF, fibroblast growth factor; G6b‐B‐R, megakaryocyte lineage‐specific immunoreceptor tyrosine‐based inhibition motif–containing receptor; IL, interleukin; PDGF, platelet derived growth factor; PRELP, proline/arginine‐rich end leucine‐rich repeat protein, Prolargin; VEGF, vascular cell endothelial cell growth factor; WARP, von Willebrand factor A domain‐related protein; α‐DG, alpha dystroglycan.…”

“… Note : Data compiled from references 7 , 12 , 13 , 19 , 20 , 21 , 22 , 23 , 24 . Table adapted from reference 25 with permission. …”

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity

“…The GAG side chains of PGs also equip them with interactive properties with a diverse range of ligands including growth factors, morphogens, and structural ECM glycoproteins which allows them to participate in a range of processes in tissue development and physiological processes that control cellular behavior. In the specific context of the brain, tissue stabilization, cellular regulation, control of ionic environments, compartmentalization, and hydration are particularly important beneficial traits displayed by PGs (Dityatev et al., 2010; Farrugia & Melrose, 2023; Hayes & Melrose, 2023; Melrose, 2023, 2024a; Melrose et al., 2021).…”