FGF-4 binds lung (bottom) but not heart (top), whereas FGF-2 binds both.

Proteoglycans on the cell surface can exhibit a baffling diversity of structures, but the relative importance of that diversity in controlling the specificity of interactions between proteins is not known. On page 845, Allen et al. demonstrate that heparan sulfate serves as a tissue-specific regulator of interactions between FGF family members and FGF receptors. Besides providing important insight into the mechanism of FGF signaling, the work suggests that specific heparan sulfate sequences on a cell's surface can determine the cell's ability to respond to exogenous signals.

The formation of an FGF signaling complex requires that both an FGF-family protein and its receptor interact with a heparan sulfate proteoglycan, but little was known about the function of heparan sulfate in this complex. The authors probed frozen tissue sections of mouse embryos with FGF-2 and FGF-4 to detect heparan sulfate expression patterns, and also examined the ability of two FGF receptor constructs to promote FGF signaling complex formation.

FGF-2 and FGF-4 bind to many of the same tissues, but FGF-4 does not recognize heparan sulfate in the heart or major blood vessels. One of the two FGF receptor constructs also demonstrated much less promiscuous complex-forming activity than the other. The results suggest that FGF-2, FGF-4, and FGF receptors recognize different forms of heparan sulfate that are expressed in a tissue-specific manner.The authors have now expanded their analysis to include five different FGFs and four different receptors, and have determined that both FGFs and FGF receptors seek specific binding sites on heparan sulfate, displaying a binding pattern that changes during the course of development. Because heparan sulfate is also a ligand for a variety of growth factors and viruses, the findings imply a wide range of specific functions for proteoglycans. ▪