Monomer Complexes of Basic Fibroblast Growth Factor and Heparan Sulfate Oligosaccharides Are the Minimal Functional Unit for Cell Activation

Pye, David; Gallagher, John T.

doi:10.1074/jbc.274.19.13456

Cited by 52 publications

(35 citation statements)

References 59 publications

(58 reference statements)

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“…For instance, in a recent study, it was found that covalently linked complexes of monomeric FGF with a pool of heparin dodecasaccharides were able to promote cell proliferation in vitro (50). However, as observed in that study, the covalent FGF⅐HLGAG complex was less active than uncomplexed FGF in promoting [ 3 H]thymidine incorporation.…”

Section: Figmentioning

confidence: 42%

See 1 more Smart Citation

Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling

Kwan

Venkataraman

Shriver

et al. 2001

Journal of Biological Chemistry

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For a number of growth factors and cytokines, ligand dimerization is believed to be central to the formation of an active signaling complex. In the case of fibroblast growth factor-2 (FGF2) signaling, heparin/heparan sulfate-like glycosaminoglycans (HLGAGs) are involved through interaction with both FGF2 and its receptors (FGFRs) in assembling a tertiary complex and modulating FGF2 activity. Biochemical data have suggested different modes of HLGAG-induced FGF2 dimerization involving specific protein-protein contacts. In addition, several recent x-ray crystallography studies of FGF⅐FGFR and FGF⅐FGFR⅐HLGAG complexes have revealed other modes of molecular assemblage, with no FGF-FGF contacts. All these different biochemical and structural findings have clarified less and in fact raised more questions as to which mode of FGF2 dimerization, if any, is essential for signaling. In this study, we address the issue of FGF2 dimerization in signaling using a combination of biochemical, biophysical, and site-directed mutagenesis approaches. Our findings presented here provide direct evidence of FGF2 dimerization in mediating FGF2 signaling.Fibroblast growth factors (FGFs) 1 are involved in a wide range of physiological processes, including morphogenesis, as well as disease processes such as tumor angiogenesis (1-3). The FGF family consists of at least 20 members, including the well characterized acidic FGF (FGF1) and basic FGF (FGF2), both of which are potent mitogens of many cell types (4, 5). FGF signaling is mediated primarily through high affinity interactions with cell-surface FGF receptors (FGFRs), transmembrane polypeptides composed of immunoglobulin-like and tyrosine kinase domains (6, 7). FGF binding to different isoforms of FGFR is believed to trigger receptor dimerization, followed by transphosphorylation of specific tyrosine residues (8). In turn, phosphorylated tyrosine residues activate other signaling proteins, leading to cell proliferation, migration, and survival.For proper presentation to FGFR, FGF2 and other members of the FGF family interact with heparin/heparan sulfate-like glycosaminoglycans (HLGAGs). Consisting of a disaccharide repeat of glucosamine and uronic acid, HLGAGs are heterogeneous in length (10 -100 disaccharide units) and chemical composition (including differential sulfation, acetylation, and epimerization of each disaccharide unit) (9 -12). Found in the extracellular matrix and on the cell surface as part of proteoglycans, HLGAGs modulate FGF2 activity by low affinity interactions with specific FGF2-and FGFR-binding sites (13-15), facilitating FGF2 binding to FGFR. HLGAGs promote FGF2-induced activation of FGFR through a number of mechanisms, including regulating the diffusion rate of FGF2 (16, 17) and possibly dictating the specificity of FGF2-FGFR binding through interactions with both .Another hypothesis is that FGF2 binding to HLGAGs induces ligand oligomerization, which in turn induces dimerization and transphosphorylation of FGFR. Biochemical studies have demonstrated that HLGAGs...

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Section: Figmentioning

confidence: 42%

“…In addition, it must be noted that other studies have suggested that monomeric forms of FGF2 may form active signaling complexes (49,50). For instance, in a recent study, it was found that covalently linked complexes of monomeric FGF with a pool of heparin dodecasaccharides were able to promote cell proliferation in vitro (50).…”

Section: Figmentioning

confidence: 99%

Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling

Kwan

Venkataraman

Shriver

et al. 2001

Journal of Biological Chemistry

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“…Moreover, in GAG-protein cross-linking experiments it was found that 1:1 covalent complexes were formed between FGF2 and S-domains isolated from HS. These complexes were biologically active, suggesting that the minimum mitogenic unit is a single FGF2 bound to a saccharide activator (51).…”

Section: Dimerization Models and Crystal Structuresmentioning

confidence: 99%

Heparan sulfate: growth control with a restricted sequence menu

Gallagher¹

2001

J. Clin. Invest.

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104

146

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“…Despite its simplicity, this model is controversial. For example, it was recently shown that the minimal subunit for FGFR-1 activation is a monomer, suggesting that the HS provides a template for the FGF-2 and FGFR-1 interaction and does not act by oligomerizing either ligand or receptor (17). Similarly, for the FGF-7 receptor, heparin or HSPG-induced oligomerization of either FGF-1 or -7 does not correlate with biological activity, supporting the model that HSPG-induced ligand oligomerization is not critical in formation of the receptor-ligand complex (18).…”

Section: Hspgs Regulate Ligand-receptor Encountersmentioning

confidence: 99%

Cell Surface Heparan Sulfate Proteoglycans: Selective Regulators of Ligand-Receptor Encounters

Park¹,

Reizes

Bernfield

2000

Journal of Biological Chemistry

340

270

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Cell surface heparan sulfate proteoglycans (HSPGs), 1 substantially more abundant than most receptors, modulate encounters of extracellular protein ligands with their receptors by forming HSprotein complexes. Two gene families account for most cell surface HSPGs. Both consist of discrete core proteins covalently attached to two or three chains of HS, an N-and O-sulfated linear polysaccharide of repeating disaccharides containing N-acetylglucosamine (GlcNAc) and uronic acid (glucuronic acid (GlcA) or iduronic acid (IdoUA)). The syndecan family was the first discovered, which in mammals contains four gene products with distinctive extracellular domains (ectodomains) and highly conserved short cytoplasmic domains. These apparently extended proteins place the HS chains distal from the plasma membrane (1, 2). The syndecan family contrasts with the glypican family, which in mammals contains six gene products that are covalently linked to plasma membrane lipid by glycosylphosphatidylinositol anchor (1, 3). The glypican core proteins contain six invariant disulfide bonds, are likely to be globular, and place HS chains adjacent to the plasma membrane. Expression of both the syndecans and glypicans is extensively regulated during mouse embryogenesis and results in discrete adult expression patterns for each HSPG such that every adherent cell exhibits a distinct repertoire of cell surface HSPGs.Binding to HS chains is remarkably widespread among extracellular proteins, especially matrix proteins, proteases and their inhibitors, lipases, lipoproteins, growth factors and their binding proteins, cytokines, chemokines, collectins, and antimicrobial peptides. These proteins are involved in morphogenesis, tissue repair, energy balance, and host defense (Fig. 1). Additionally, numerous pathogens (e.g. herpes simplex virus, Neisseria, Plasmodium) bind to the cell surface via HS (4). Importantly, many of these ligand-HS interactions are essentially identical from Drosophila to the mouse, including those involved in generation of the basic metazoan body plan, e.g. dpp (bone morphogenetic proteins 2-4), wg (Wnt-1), and sog (chordin).Formation of the complexes can enhance or reduce receptor activation, often depending on the concentrations of ligand, receptor, and HSPG. The HS chains catalyze encounters between ligand and signaling receptor by bringing them together. Because binding to the HS chain reduces the dimensionality of this interaction from three (when the ligand is soluble) to two (when the ligand is bound to the HS chain), interaction could result from a localized increase in ligand concentration at optimal HS concentrations (5). However, at HS levels lower or higher than optimal, the effective ligand concentration for engaging the receptor will fall, potentially accounting for the bell-shaped activity curve typically seen experimentally when HSPG (or heparin) concentrations are varied. The curve may be concave or convex depending on whether ligand binding to the HSPG is inhibitory or stimulatory (6). Furthermore, the cytop...

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Monomer Complexes of Basic Fibroblast Growth Factor and Heparan Sulfate Oligosaccharides Are the Minimal Functional Unit for Cell Activation

Cited by 52 publications

References 59 publications

Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling

Probing Fibroblast Growth Factor Dimerization and Role of Heparin-like Glycosaminoglycans in Modulating Dimerization and Signaling

Heparan sulfate: growth control with a restricted sequence menu

Cell Surface Heparan Sulfate Proteoglycans: Selective Regulators of Ligand-Receptor Encounters

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