Role of heparan sulfate as a tissue-specific regulator of FGF-4 and FGF receptor recognition

FGF signaling uses receptor tyrosine kinases that form high-affinity comple xes with FGFs and heparan sulfate (HS) proteoglycans at the cell surface. I t is hypothesized that assembly of these complexes requires simultaneous re cognition of distinct sulfation patterns within the HS chain by FGF and the FGF receptor (FR), suggesting that tissue-specific HS synthesis may regula te FGF signaling. To address this, FGF-2 and FGF-4, and extracellular domai n constructs of FR1-IIIc (FR1 c) and FR2-IIIc (FR2c), were used to probe fo r tissue-specific HS in embryonic day 18 mouse embryos. Whereas FGF-2 binds HS ubiquitously, FGF-4 exhibits a restricted pattern, failing to bind HS i n the heart and blood vessels and failing to activate signaling in mouse ao rtic endothelial cells. This suggests that FGF-4 seeks a specific HS sulfat ion pattern, distinct from that of FGF-2, which is not expressed in most va scular tissues. Additionally, whereas FR2c binds all FCF-4-HS complexes, FR 1c fails to bind FGF-4-HS in most tissues, as well as in Raji-SI cells expr essing syndecan-1. Proliferation assays using BaF3 cells expressing either FR1 c or FR2c support these results. This suggests that FGF and FR recognit ion of specific HS sulfation patterns is critical for the activation of FGF signaling, and that synthesis of these patterns is regulated during embryo nic development.