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Published 26 November 2001. doi:10.1083/jcb.200106075
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© The Rockefeller University Press, 0021-9525/2001/11/845 $5.00
The Journal of Cell Biology, Volume 155, Number 5, November 26, 2001 845-858

Article

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



Benjamin L. Allen, Mark S. Filla and Alan C. Rapraeger

Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, WI 53706

Address correspondence to Alan C. Rapraeger, Dept. of Pathology and Laboratory Medicine, University of Wisconsin–Madison, 1300 University Ave., Madison, WI 53706. Tel.: (608) 262-7577. Fax: (608) 265-3301. E-mail: acraprae{at}facstaff.wisc.edu

FGF signaling uses receptor tyrosine kinases that form high-affinity complexes with FGFs and heparan sulfate (HS) proteoglycans at the cell surface. It is hypothesized that assembly of these complexes requires simultaneous recognition of distinct sulfation patterns within the HS chain by FGF and the FGF receptor (FR), suggesting that tissue-specific HS synthesis may regulate FGF signaling. To address this, FGF-2 and FGF-4, and extracellular domain constructs of FR1-IIIc (FR1c) and FR2-IIIc (FR2c), were used to probe for 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 in the heart and blood vessels and failing to activate signaling in mouse aortic endothelial cells. This suggests that FGF-4 seeks a specific HS sulfation pattern, distinct from that of FGF-2, which is not expressed in most vascular tissues. Additionally, whereas FR2c binds all FGF-4–HS complexes, FR1c fails to bind FGF-4–HS in most tissues, as well as in Raji-S1 cells expressing syndecan-1. Proliferation assays using BaF3 cells expressing either FR1c or FR2c support these results. This suggests that FGF and FR recognition of specific HS sulfation patterns is critical for the activation of FGF signaling, and that synthesis of these patterns is regulated during embryonic development.

Key Words: heparan sulfate proteoglycan; fibroblast growth factors; FGF receptors; development; sulfation


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