ArticleThe Journal of biological chemistry2010
Influence of heparin mimetics on assembly of the FGF.FGFR4 signaling complex.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 33 citations in OpenAlex.
- NMR resonance assignment of a fibroblast growth factor 8 splicing isoform b.Biomolecular NMR assignments · 2023Article
- NMR Characterization of the Interactions Between Glycosaminoglycans and Proteins.Frontiers in molecular biosciences · 2021Review
- Review
- Effect of extension of the heparin binding pocket on the structure, stability, and cell proliferation activity of the human acidic fibroblast growth factor.Biochemistry and biophysics reports · 2018Article
- A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration.Cardiovascular research · 2017Article
- Interactions between a Heparin Trisaccharide Library and FGF-1 Analyzed by NMR Methods.International journal of molecular sciences · 2017Article
- Computational drill down on FGF1-heparin interactions through methodological evaluation.Glycoconjugate journal · 2017Article
- Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors.Progress in biophysics and molecular biology · 2015Review
- Cooperative heparin-mediated oligomerization of fibroblast growth factor-1 (FGF1) precedes recruitment of FGFR2 to ternary complexes.Biophysical journal · 2013Article
- Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site.Journal of medicinal chemistry · 2013Article
- Proteoglycan sequence.Molecular bioSystems · 2012Review
- Novel regulation of fibroblast growth factor 2 (FGF2)-mediated cell growth by polysialic acid.The Journal of biological chemistry · 2012Article
- Chlamydia trachomatis co-opts the FGF2 signaling pathway to enhance infection.PLoS pathogens · 2011Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
Abstract
Fibroblast growth factor (FGF) signaling regulates mammalian development and metabolism, and its dysregulation is implicated in many inherited and acquired diseases, including cancer. Heparan sulfate glycosaminoglycans (HSGAGs) are essential for FGF signaling as they promote FGF.FGF receptor (FGFR) binding and dimerization. Using novel organic synthesis protocols to prepare homogeneously sulfated heparin mimetics (HM), including hexasaccharide (HM(6)), octasaccharide (HM(8)), and decasaccharide (HM(10)), we tested the ability of these HM to support FGF1 and FGF2 signaling through FGFR4. Biological assays show that both HM(8) and HM(10) are significantly more potent than HM(6) in promoting FGF2-mediated FGFR4 signaling. In contrast, all three HM have comparable activity in promoting FGF1.FGFR4 signaling. To understand the molecular basis for these differential activities in FGF1/2.FGFR4 signaling, we used NMR spectroscopy, isothermal titration calorimetry, and size-exclusion chromatography to characterize binding interactions of FGF1/2 with the isolated Ig-domain 2 (D2) of FGFR4 in the presence of HM, and binary interactions of FGFs and D2 with HM. Our data confirm the existence of both a secondary FGF1.FGFR4 interaction site and a direct FGFR4.FGFR4 interaction site thus supporting the formation of the symmetric mode of FGF.FGFR dimerization in solution. Moreover, our results show that the observed higher activity of HM(8) relative to HM(6) in stimulating FGF2.FGFR4 signaling correlates with the higher affinity of HM(8) to bind and dimerize FGF2. Notably FGF2.HM(8) exhibits pronounced positive binding cooperativity. Based on our findings we propose a refined symmetric FGF.FGFR dimerization model, which incorporates the differential ability of HM to dimerize FGFs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.