Coreceptor functions of cell surface heparan sulfate proteoglycans

Abstract

Receptor-ligand interactions play an important role in many biological processes by triggering specific cellular responses. These interactions are frequently regulated by coreceptors that facilitate, alter, or inhibit signaling. Coreceptors work in parallel with other specific and accessory molecules to coordinate receptor-ligand interactions. Cell surface heparan sulfate proteoglycans (HSPGs) function as unique coreceptors because they can bind to many ligands and receptors through their HS and core protein motifs. Cell surface HSPGs are typically expressed in abundance of the signaling receptors and, thus, are capable of mediating the initial binding of ligands to the cell surface. HSPG coreceptors do not possess kinase domains or intrinsic enzyme activities and, for the most part, binding to cell surface HSPGs does not directly stimulate intracellular signaling. Because of these features, cell surface HSPGs primarily function as coreceptors for many receptor-ligand interactions. Given that cell surface HSPGs are widely conserved, they likely serve fundamental functions to preserve basic physiological processes. Indeed, cell surface HSPGs can support specific cellular interactions with growth factors, morphogens, chemokines, extracellular matrix (ECM) components, and microbial pathogens and their secreted virulence factors. Through these interactions, HSPG coreceptors regulate cell adhesion, proliferation, migration, and differentiation, and impact the onset, progression, and outcome of pathophysiological processes, such as development, tissue repair, inflammation, infection, and tumorigenesis. This review seeks to provide an overview of the various mechanisms of how cell surface HSPGs function as coreceptors.

Keywords: coreceptor; heparan sulfate; proteoglycan; receptor-ligand interaction; signaling.

Figure 1.

Schematic overview of coreceptor functions of cell surface heparan sulfate proteoglycans (HSPGs) I. A: interaction with soluble ligands: cell surface HSPGs capture soluble ligands, increase their local concentration, and increase their availability for signaling receptors. B: interaction with extracellular matrix (ECM) components: cell surface HSPG binding facilitates binding of ECM components to integrin receptors in a heparan sulfate (HS)-dependent manner. C: formation of ligand/receptor/HSPG complexes: cell surface HSPGs bind to both ligands and signaling receptors to form a tertiary receptor complex. D: oligomerization of ligands: cell surface HSPGs provide a HS platform with multiple binding sites for ligand oligomerization, and ligand oligomers interact more avidly with signaling receptors.

Figure 2.

Schematic overview of coreceptor functions of cell surface heparan sulfate proteoglycans (HSPGs) II. A: interaction with receptors: cell surface HSPGs can enhance signaling by directly regulating receptor distribution, stability, oligomerization state, and activity. B: trans coreceptors: cell surface HSPGs present ligands to receptors on neighboring cells thereby functioning as in trans coreceptors. C: interaction with intracellular molecules: cell surface HSPGs with cytoplasmic domains can enhance receptor signaling through recruitment of intracellular signaling molecules to the receptor complex. D: intracellular trafficking of ligands: HSPG coreceptors control ligand availability at the cell surface through endocytosis of ligands and either recycling them back to the cell surface of transporting them to lysosomes for degradation. E: formation of ligand gradients: cell surface HSPGs immobilize morphogens to form morphogen gradients during development and immobilize chemokines to form haptotactic gradients to guide the directional migration of leukocytes.

Figure 3.

Cell surface syndecan (SDC)1 and exogenous heparan sulfate (HS) enhance growth factor signaling in mouse embryonic fibroblasts (MEFs) and mesenchymal stem cells (MSCs). A: MEFs isolated from Wt or syndecan-1 null (Sdc1^−/−) mice on C57BL/6J were stimulated with fibroblast growth factor (FGF)2 at the indicated concentrations for 30 min at 37°C. Whole cell lysates were Western blotted for phospho-p44/42 (Thr202/Tyr204) (p-p44/42) and total p44/42 (Cell Signaling Technology, Danvers, MA). B: MSCs isolated from inguinal fat pads of Wt C57BL/6J mice were incubated with HB-EGF without or with HS or chondroitin sulfate (CS) for 30 min at 37°C. Whole cell lysates were Western blotted for p-p44/42 and total p44/42.