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Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor.
Biochemistry. 1999 Feb 09; 38(6):1765-71.B

Abstract

Keratinocyte growth factor (KGF) is an unusual fibroblast growth factor (FGF) family member in that its activity is largely restricted to epithelial cells, and added heparin/heparan sulfate inhibits its activity in most cell types. The effects of heparan sulfate proteoglycan (HSPG) on binding and signaling by acidic FGF (aFGF) and KGF via the KGFR were studied using surface-bound and soluble receptor isoforms expressed in wild type and mutant Chinese hamster ovary (CHO) cells lacking HSPG. Low concentrations of added heparin (1 microgram/mL) enhanced the affinity of ligand binding to surface-bound KGFR in CHO mutants, as well as ligand-stimulated MAP kinase activation and c-fos induction, but had little effect on binding or signaling in wild type CHO cells. Higher heparin concentrations inhibited KGF, but not aFGF, binding and signaling. In addition to the known interaction between HSPG and KGF, we found that the KGFR also bound heparin. The biphasic effect of heparin on KGF, but not aFGF, binding and signaling suggests that occupancy of the HSPG binding site on the KGFR may specifically inhibit KGF signaling. In contrast to events on the cell surface, added heparin was not required for high-affinity soluble KGF-KGFR interaction. These results suggest that high-affinity ligand binding is an intrinsic property of the receptor, and that the difference between the HSPG-dependent ligand binding to receptor on cell surfaces and the HSPG-independent binding to soluble receptor may be due to other molecule(s) present on cell surfaces.

Authors+Show Affiliations

Laboratory of Cellular and Molecular Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10026256

Citation

LaRochelle, W J., et al. "Heparan Sulfate Proteoglycan Modulates Keratinocyte Growth Factor Signaling Through Interaction With Both Ligand and Receptor." Biochemistry, vol. 38, no. 6, 1999, pp. 1765-71.
LaRochelle WJ, Sakaguchi K, Atabey N, et al. Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor. Biochemistry. 1999;38(6):1765-71.
LaRochelle, W. J., Sakaguchi, K., Atabey, N., Cheon, H. G., Takagi, Y., Kinaia, T., Day, R. M., Miki, T., Burgess, W. H., & Bottaro, D. P. (1999). Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor. Biochemistry, 38(6), 1765-71.
LaRochelle WJ, et al. Heparan Sulfate Proteoglycan Modulates Keratinocyte Growth Factor Signaling Through Interaction With Both Ligand and Receptor. Biochemistry. 1999 Feb 9;38(6):1765-71. PubMed PMID: 10026256.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor. AU - LaRochelle,W J, AU - Sakaguchi,K, AU - Atabey,N, AU - Cheon,H G, AU - Takagi,Y, AU - Kinaia,T, AU - Day,R M, AU - Miki,T, AU - Burgess,W H, AU - Bottaro,D P, PY - 1999/2/23/pubmed PY - 1999/2/23/medline PY - 1999/2/23/entrez SP - 1765 EP - 71 JF - Biochemistry JO - Biochemistry VL - 38 IS - 6 N2 - Keratinocyte growth factor (KGF) is an unusual fibroblast growth factor (FGF) family member in that its activity is largely restricted to epithelial cells, and added heparin/heparan sulfate inhibits its activity in most cell types. The effects of heparan sulfate proteoglycan (HSPG) on binding and signaling by acidic FGF (aFGF) and KGF via the KGFR were studied using surface-bound and soluble receptor isoforms expressed in wild type and mutant Chinese hamster ovary (CHO) cells lacking HSPG. Low concentrations of added heparin (1 microgram/mL) enhanced the affinity of ligand binding to surface-bound KGFR in CHO mutants, as well as ligand-stimulated MAP kinase activation and c-fos induction, but had little effect on binding or signaling in wild type CHO cells. Higher heparin concentrations inhibited KGF, but not aFGF, binding and signaling. In addition to the known interaction between HSPG and KGF, we found that the KGFR also bound heparin. The biphasic effect of heparin on KGF, but not aFGF, binding and signaling suggests that occupancy of the HSPG binding site on the KGFR may specifically inhibit KGF signaling. In contrast to events on the cell surface, added heparin was not required for high-affinity soluble KGF-KGFR interaction. These results suggest that high-affinity ligand binding is an intrinsic property of the receptor, and that the difference between the HSPG-dependent ligand binding to receptor on cell surfaces and the HSPG-independent binding to soluble receptor may be due to other molecule(s) present on cell surfaces. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/10026256/Heparan_sulfate_proteoglycan_modulates_keratinocyte_growth_factor_signaling_through_interaction_with_both_ligand_and_receptor_ L2 - https://doi.org/10.1021/bi982092z DB - PRIME DP - Unbound Medicine ER -