Molecular functions of syndecan-1 in disease

Abstract

Syndecan-1 is a cell surface heparan sulfate proteoglycan that binds to many mediators of disease pathogenesis. Through these molecular interactions, syndecan-1 can modulate leukocyte recruitment, cancer cell proliferation and invasion, angiogenesis, microbial attachment and entry, host defense mechanisms, and matrix remodeling. The significance of syndecan-1 interactions in disease is underscored by the striking pathological phenotypes seen in the syndecan-1 null mice when they are challenged with disease-instigating agents or conditions. This review discusses the key molecular functions of syndecan-1 in modulating the onset, progression, and resolution of inflammatory diseases, cancer, and infection.

Fig. 1. Mechanisms of syndecan-1 in inflammatory diseases

A) Syndecan-1 inhibits leukocyte adhesion to activated endothelial cells by inhibiting the β2 integrin-ICAM-1 interaction. B) Endothelial syndecan-1 binds to chemokines and generates a chemokine gradient that facilitates the transendothelial migration of leukocytes. Cell surface syndecan-1 is shown in both the basal and apical surfaces as the normal polarized expression of syndecan-1 on the basolateral surface is disrupted by injury. C) MMP-7-mediated syndecan-1 shedding in alveolar epithelial cells generates a chemokine gradient for the transepithelial migration of neutrophils. D) Syndecan-1 shedding resolves chemokine gradients by removing chemokines tethered to cell surface syndecan-1 or by displacing chemokines tethered to other HSPGs through the release of unbound syndecan-1 ectodomains.

Fig. 2. Mechanisms of syndecan-1 in cancer

A) In myeloma, cell surface syndecan-1 binds to HGF via HS chains and promotes Met activation, leading to myeloma cell growth and survival. Shed syndecan-1 also binds to and presents HGF to osteoblasts. This results in the activation of IL-11 and upregulation of RANKL, leading to inhibition of bone formation and promotion of bone resorption. B) Cell surface syndecan-1 mediates cancer cell adhesion to the ECM and retards cancer cell migration. C) Syndecan-1 shedding releases the VEGF-syndecan-1 ectodomain complex, which binds to and activates VEGFRs on endothelial cells. Syndecan-1 can also activate αvβ3 integrin, which mediates the activation of VEGF signaling. This transactivation mechanism stimulates endothelial cell sprouting and subsequent angiogenesis.

Fig. 3. Mechanisms of syndecan-1 in infectious diseases

A) Syndecan-1 is subverted by many microbial pathogens as a coreceptor that localizes pathogens to the host cell surface and promotes their interactions with specific entry receptors. B) Select pathogens, such as N. gonorrhoeae, can use cell surface syndecan-1 as a direct entry receptor by stimulating intracellular signaling mediated by the syndecan-1 cytoplasmic domain. C) Several bacterial pathogens induce syndecan-1 shedding and exploit the capacity of syndecan-1 ectodomains to inhibit the antibacterial mechanisms of neutrophils and antimicrobial peptides.