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 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.
Allen
B L
BL
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Filla
M S
MS
Rapraeger
A C
AC
D000469:Alkaline Phosphatase; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000196:embryology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D058851:GPI-Linked Proteins; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000737:chemistry / Q000166:cytology / Q000196:embryology
D000469:Alkaline Phosphatase; D016222:Fibroblast Growth Factor 2; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors; D058851:GPI-Linked Proteins; D006493:Heparin; D006497:Heparan Sulfate; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C496446:Fgf4 protein, mouse; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C019839:alkaline phosphatase, placental