High-affinity Binding of Basic Fibroblast Growth Factor and Platelet-derived Growth Factor-AA to the Core Protein of the NG2 Proteoglycan

Goretzki, Lothar; Burg, Michael A.; Grako, Kathryn A.; Stallcup, William B.

doi:10.1074/jbc.274.24.16831

Cited by 188 publications

(176 citation statements)

References 43 publications

(41 reference statements)

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“…This possibility seems to be unlikely, because FGF-2 binds to the HS chains and not the core protein of syndecan-3 (37). It is worth mentioning, however, that FGF-2 does bind with high affinity to the core protein of the transmembrane chondroitin sulfate proteoglycan NG2 (38) and another family member, FGF-7, binds to the core protein of perlecan (39).…”

Section: Syndecan-3 and Chondrocyte Proliferationmentioning

confidence: 91%

Syndecan-3 Is a Selective Regulator of Chondrocyte Proliferation

Kirsch

Koyama²,

Liu³

et al. 2002

Journal of Biological Chemistry

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Chondrocyte proliferation is important for skeletal development and growth, but the mechanisms regulating it are not completely clear. Previously, we showed that syndecan-3, a cell surface heparan sulfate proteoglycan, is expressed by proliferating chondrocytes in vivo and that proliferation of cultured chondrocytes in vitro is sensitive to heparitinase treatment. To further establish the link between syndecan-3 and chondrocyte proliferation, additional studies were carried out in vivo and in vitro. We found that the topographical location of proliferating chondrocytes in developing chick long bones changes with increasing embryonic age and that syndecan-3 gene expression changes in a comparable manner. For in vitro analysis, mitotically quiescent chondrocytes were exposed to increasing amounts of fibroblast growth factor-2 (FGF-2). Proliferation was stimulated by as much as 8 -10-fold within 24 h; strikingly, this stimulation was significantly prevented when the cells were treated with both fibroblast growth factor-2 (FGF-2) and antibodies against syndecan-3 core protein. This neutralizing effect was dose-dependent and elicited a maximum of 50 -60% inhibition. To establish specificity of neutralizing effect, cultured chondrocytes were exposed to FGF-2, insulin-like growth factor-1, or parathyroid hormone, all known mitogens for chondrocytes. The syndecan-3 antibodies interfered only with FGF-2 mitogenic action, but not that of insulin-like growth factor-1 or parathyroid hormone. Protein cross-linking experiments indicated that syndecan-3 is present in monomeric, dimeric, and oligomeric forms on the chondrocyte surface. In addition, molecular modeling indicated that contiguous syndecan-3 molecules might form stable complexes by parallel pairing of ␤-sheet segments within the ectodomain of the core protein. In conclusion, the results suggest that syndecan-3 is a direct and selective regulator of the mitotic behavior of chondrocytes and its role may involve formation of dimeric/oligomeric structures on their cell surface.Chondrocytes constitute the embryonic cartilaginous skeleton, the growth plates of fetal and postnatal skeletal elements, and permanent cartilages such as articular cartilage, nasal septum, and tracheal rings. In these various structures and locations, chondrocytes exhibit characteristic and strictly controlled mitotic activity, and this activity has diverse roles and implications. For example, in the growth plate chondrocyte proliferation is topographically limited to a narrow zone flanked by a resting zone of quiescent cells and an underlying zone of postmitotic prehypertrophic cells (1). A main role for chondrocyte proliferation in the growth plate is to counterbalance the loss of hypertrophic chondrocytes occurring at the chondro-osseous border and their replacement by endochondral bone cells. A second important role is to determine the overall rates of skeletal growth, as illustrated by the different rates of proliferation displayed by chondrocytes in long bones elongating at different rates ...

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Section: Syndecan-3 and Chondrocyte Proliferationmentioning

confidence: 91%

Syndecan-3 Is a Selective Regulator of Chondrocyte Proliferation

Kirsch

Koyama²,

Liu³

et al. 2002

Journal of Biological Chemistry

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“…The core proteins of some proteoglycans (e.g. NG2 and phosphacan) bind to FGF2 (37,38). Direct core protein interactions with signaling components might be lost upon tryptic release of the proteoglycan from the cell surface, explaining the failure of these soluble forms.…”

Section: Fig 8 Fgfr1-activation By Purified Hs Chains and Chain Clumentioning

confidence: 99%

Membrane Heparan Sulfate Proteoglycan-supported FGF2-FGFR1 Signaling

Zhang

Coomans

Gourichon

2001

Journal of Biological Chemistry

103

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signaling. Extrapolating from current structural models, we suggest that FGFR dimerization and autophosphorylation is supported by cooperative "heparin-like end structures," and that cell surface association and concentration compensate for the relative scarcity of such end structures in native HSPGs. In this model, "proteolytic" shedding of heparan sulfate would act as a diluting, down-regulatory mechanism, while "heparanolytic" shedding might act as an up-regulatory mechanism, by increasing the concentration of these end structures. Fibroblast growth factors (FGFs)1 bind not only to their cognate receptors (FGFRs) but also to heparan sulfate proteoglycans (HSPGs). HSPGs are associated with the cell surface of many, if not most, cell types. Most known HSPG functions are contributed by the interactions of the heparan sulfate (HS) chains of these molecules. Besides growth factors, these HSPGs interact with various adhesion molecules, protease inhibitors, and enzymes, modifying the spatial distributions and activities of these ligands. Among FGFs, the interaction with FGF2 has been studied most intensively, and it is now generally accepted that HSPGs play important roles in FGF2 signaling. Initially, the association of FGF2 with HS has been proposed to protect this FGF from proteolysis and thermal denaturation (1, 2) and to serve as a reservoir of growth factor that can be released by enzymes that degrade the proteoglycans (1). Later, HSPGs were identified as co-receptors for FGF2, strongly promoting FGF-FGFR binding and the subsequent activation of the receptor (3, 4). Recently, genetic studies in Drosophila provided compelling evidence that HSPGs are essential for FGF signaling in vivo (5).Although the importance of HSPG in FGF-signaling is well documented, the nature of the "co-receptor" and the precise mechanisms at work are less well characterized. Distinctive core protein structures define two major families of cell surfaceassociated HSPGs: syndecans and glypicans (6). Prior work from our laboratory showed that syndecans and glypican-1 stimulate FGF2-FGFR1 interaction and signaling in K562 cells, at least when co-expressed with receptor in these cells (4). This agrees with the work of other groups, showing that cell surface syndecan-1 from Raji cells acts as a positive regulator of FGF2 binding and signaling (7), that syndecan-2 on human macrophages promotes FGF2-mediated proliferation (8), and that glypican-1 can stimulate FGF2 signaling (9, 10). Meanwhile, there are also other, contradictory reports. Syndecans and glypican-1 purified from human lung fibroblast extracts are unable to promote high affinity binding of FGF2 to FGFR1 (11), overexpression of syndecan-1 in NIH 3T3 cells inhibits FGF2-induced proliferation (12), and HSPGs purified from endothelial secretions prevent FGF2 binding to vascular smooth muscle cells and inhibit FGF2-induced mitogenesis (13). One possible explanation for this discrepancy is that the HSPGs were from different sources and might have had different compositions. It is well k...

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“…Alternatively, the stable deposition of QBRICK͞Frem1, Fras1, and Frem2 in the basement membrane may be necessary for the propagation of morphogenetic factor signals, as seen in the requirement of heparan sulfate chains by FGF for effective signal transduction through the FGF receptor (16). Because the CSPG repeats of NG2 bind PDGF-AA and basic FGF (17), these Fraser syndrome-associated 12-CSPG-containing proteins may bind soluble ligands and present them to their receptors on adjacent cells, facilitating epithelial-mesenchymal interactions. The wide spectrum of dysmorphogenesis observed in Fraser syndrome model mice suggests that QBRICK͞Frem1, Fras1, and Frem2 function not as individual ligands in a specific signaling pathway but as part of the fundamental machinery governing epithelial-mesenchymal interactions by orchestrating intercellular signaling pathways.…”

Section: Reciprocal Requirement Of Qbrick͞frem1 For the Stable Basementmentioning

confidence: 99%

Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects

Kiyozumi

Sugimoto

Sekiguchi

2006

Proc. Natl. Acad. Sci. U.S.A.

108

178

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An emerging family of extracellular matrix proteins characterized by 12 consecutive CSPG repeats and the presence of Calx-␤ motif(s) includes Fras1, QBRICK͞Frem1, and Frem2. Mutations in the genes encoding these proteins have been associated with mouse models of Fraser syndrome, which is characterized by subepidermal blistering, cryptophthalmos, syndactyly, and renal dysmorphogenesis. Here, we report that all of these proteins are localized to the basement membrane, and that their basement membrane localization is simultaneously impaired in Fraser syndrome model mice. In Frem2 mutant mice, not only Frem2 but Fras1 and QBRICK͞Frem1 were depleted from the basement membrane zone. This coordinated reduction in basement membrane deposition was also observed in another Fraser syndrome model mouse, in which GRIP1, a Fras1-and Frem2-interacting adaptor protein, is primarily affected. Targeted disruption of Qbrick͞Frem1 also resulted in diminished expression of Fras1 and Frem2 at the epidermal basement membrane, confirming the reciprocal stabilization of QBRICK͞ Frem1, Fras1, and Frem2 in this location. When expressed and secreted by transfected cells, these proteins formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane is due to complex formation. Given the close association of Fraser syndrome phenotypes with defective epidermal-dermal interactions, the coordinated assembly of three Fraser syndrome-associated proteins at the basement membrane appears to be instrumental in epidermal-dermal interactions during morphogenetic processes.epithelial-mesenchymal interaction ͉ gene targeting ͉ morphogenesis T he extracellular matrix (ECM) is an insoluble supramolecular complex surrounding metazoan cells that is often fibrous or sheet-like. The ECM functions in the control of cellular behaviors, including migration, proliferation, and differentiation, and mediates intercellular communication, as in epithelialmesenchymal interactions; both of these functions are critical during development. Because individual ECM components often function in combination with other ECM components and soluble factors, genetic disorders of the ECM are often linked to severe developmental abnormalities.

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High-affinity Binding of Basic Fibroblast Growth Factor and Platelet-derived Growth Factor-AA to the Core Protein of the NG2 Proteoglycan

Abstract: Due to their structural complexity, proteoglycans are highly interactive macromolecules that participate in a broad range of cell-cell and cell-matrix interactions, including regulation of cell adhesion, proliferation, motility, and differentiation (Refs.

Cited by 188 publications

References 43 publications

Syndecan-3 Is a Selective Regulator of Chondrocyte Proliferation

Syndecan-3 Is a Selective Regulator of Chondrocyte Proliferation

Membrane Heparan Sulfate Proteoglycan-supported FGF2-FGFR1 Signaling

Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects

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