Specificity for Fibroblast Growth Factors Determined by Heparan Sulfate in a Binary Complex with the Receptor Kinase Export

@article{citeulike:484907, abstract = {A divalent cation-dependent association between heparin or heparan sulfate and the ectodomain of the FGF receptor kinase (FGFR) restricts FGF-independent-phosphorylation and supports the binding of activating FGF to self-associated FGFR. Here we show that in contrast to heparin, cellular heparan sulfate forms a binary complex with FGFR that discriminates between FGF-1 and FGF-2. FGFR type 4 (FGFR4) in liver parenchymal cells binds only FGF-1, whereas FGFR1 binds FGF-1 and FGF-2 equally. Cell-free complexes of heparin and recombinant FGFR4 bound FGF-1 and FGF-2 equally. However, in contrast to FGFR1, when recombinant FGFR4 was expressed back in epithelial cells by transfection, it failed to bind FGF-2 unless heparan sulfate was depressed by chlorate or heparinase treatment. Isolated heparan sulfate proteoglycan (HSPG) from liver cells in cell-free complexes with FGFR4 restored the specificity for FGF-1 and supported the binding of both FGF-1 and FGF-2 when complexed with FGFR1. In contrast, FGF-2 bound equally well to complexes of both FGFR1 and FGFR4 formed with endothelial cell-derived HSPG, but the endothelial HSPG was deficient for the binding of FGF-1 to both FGFR complexes. These data suggest that a heparan sulfate subunit is a cell type- and FGFR-specific determinant of the selectivity of the FGFR signaling complex for FGF. In a physiological context, the heparan sulfate subunit may limit the redundancy among the current 18 FGF polypeptides for the 4 known FGFR.}, address = {Department of Biochemistry, Texas A\&M University, Texas A\&M University System Health Science Center, Houston, Texas 77030-3303, USA.}, author = {Kan, Mikio and Wu, Xiaochong and Wang, Fen and McKeehan, Wallace L.}, citeulike-article-id = {484907}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.274.22.15947}, citeulike-linkout-1 = {http://www.jbc.org/content/274/22/15947.abstract}, citeulike-linkout-2 = {http://www.jbc.org/content/274/22/15947.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/10336501}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=10336501}, day = {28}, doi = {10.1074/jbc.274.22.15947}, issn = {0021-9258}, journal = {Journal of Biological Chemistry}, keywords = {fgf, h, heparin, t}, month = {May}, number = {22}, pages = {15947--15952}, posted-at = {2009-10-27 02:06:05}, priority = {2}, title = {Specificity for Fibroblast Growth Factors Determined by Heparan Sulfate in a Binary Complex with the Receptor Kinase}, url = {http://dx.doi.org/10.1074/jbc.274.22.15947}, volume = {274}, year = {1999} }

TY - JOUR ID - citeulike:484907 L3 - citeulike-article-id:484907 N2 - A divalent cation-dependent association between heparin or heparan sulfate and the ectodomain of the FGF receptor kinase (FGFR) restricts FGF-independent-phosphorylation and supports the binding of activating FGF to self-associated FGFR. Here we show that in contrast to heparin, cellular heparan sulfate forms a binary complex with FGFR that discriminates between FGF-1 and FGF-2. FGFR type 4 (FGFR4) in liver parenchymal cells binds only FGF-1, whereas FGFR1 binds FGF-1 and FGF-2 equally. Cell-free complexes of heparin and recombinant FGFR4 bound FGF-1 and FGF-2 equally. However, in contrast to FGFR1, when recombinant FGFR4 was expressed back in epithelial cells by transfection, it failed to bind FGF-2 unless heparan sulfate was depressed by chlorate or heparinase treatment. Isolated heparan sulfate proteoglycan (HSPG) from liver cells in cell-free complexes with FGFR4 restored the specificity for FGF-1 and supported the binding of both FGF-1 and FGF-2 when complexed with FGFR1. In contrast, FGF-2 bound equally well to complexes of both FGFR1 and FGFR4 formed with endothelial cell-derived HSPG, but the endothelial HSPG was deficient for the binding of FGF-1 to both FGFR complexes. These data suggest that a heparan sulfate subunit is a cell type- and FGFR-specific determinant of the selectivity of the FGFR signaling complex for FGF. In a physiological context, the heparan sulfate subunit may limit the redundancy among the current 18 FGF polypeptides for the 4 known FGFR. IS - 22 JF - Journal of Biological Chemistry SN - 0021-9258 AD - Department of Biochemistry, Texas A&M University, Texas A&M University System Health Science Center, Houston, Texas 77030-3303, USA. EP - 15952 TI - Specificity for Fibroblast Growth Factors Determined by Heparan Sulfate in a Binary Complex with the Receptor Kinase VL - 274 SP - 15947 KW - fgf KW - h KW - heparin KW - t AU - Kan, Mikio AU - Wu, Xiaochong AU - Wang, Fen AU - McKeehan, Wallace PY - 1999/05/28/ UR - http://dx.doi.org/10.1074/jbc.274.22.15947 ER -