Figure 4.

Overview of the structure of syndecan 1–4 (SDC) and downstream signaling pathways

(A) Graphical depiction of a typical syndecan. Syndecans are type I, single-pass transmembrane proteoglycans. All syndecans contain HS chains covalently linked to protein core ectodomain; however, SDC1 and 3 also contain CS chains. The relative sizes of SDC 1–4 are 33, 23, 41, and 22 kDa respectively. The cytoplasmic domain contains two conserved regions, C1 and C2, separated by a variable (V1) region. The crystal structures for syndecans remain obscure because the ectodomains contain a significant amount of disorder.

(B) Syndecans serve a variety of functions but primarily act as co-receptors affecting multiple signaling pathways. SDC1 activates the IGF1 signaling pathway by stimulating docking of both IGF1-R and αvβ3/αvβ5 integrins and subsequently triggers angiogenesis. SDC4 mediates the assembly of EGFR and α6β4/α3β1 integrins which leads to downstream pro-migration signaling crucial for tumorigenesis. SDC4 binds FGF through heparan sulfate chains and is an essential co-receptor for FGF signaling. Interestingly, SDC4 can activate this signaling pathway in both an FGFR-dependent and FGFR-independent manner. Wnt signaling is modulated by SDC1 via its HS chains which bind Wnts and R-spondins to stimulate β-catenin signaling for cell growth. Syndecans play a role in recruiting pro-inflammatory molecules and modulating the progression of inflammation. This is done primarily through GAG chain binding to cytokines but there is evidence for a SDC1/IL-6 axis with the presence of a regulatory feedback loop that is yet to be elucidated. For additional details, please refer to the text. The graphic was generated with BioRender.com.