Identification of soluble forms of the fibroblast growth factor receptor in blood.

Hanneken, Anne; Ying, Wenbin; Ling, Nicholas; Baird, Andrew

doi:10.1073/pnas.91.19.9170

Cited by 83 publications

(59 citation statements)

References 54 publications

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“…Recently, three soluble FGF2-binding proteins (FGF-BPs) corresponding to the extracellular domains of FGFRs were reported to circulate in blood and to be present in the ECM even after endogenous FGF2 has been removed with 2 M NaCl (Hanneken et al, 1994(Hanneken et al, , 1995. There is the possibility that the injected 14 C-FGF2 might bind to FGF-BPs in the blood and be rapidly targeted to the ECM.…”

Section: Hspg Regulates the Bioavailability Of Fgf2 In Vivo 79mentioning

confidence: 99%

In Vivo Involvement of Heparan Sulfate Proteoglycan in the Bioavailability, Internalization, and Catabolism of Exogenous Basic Fibroblast Growth Factor

et al. 1999

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The in vivo bioavailability of exogenous fibroblast growth factor 2 (FGF2) was studied after i.v. injection of uniformly 14 C-labeled FGF2 into young rats.14 C-FGF2 was rapidly accumulated in almost all solid organs within 5 min. After 30 min, more than 65% of FGF2 was retained in liver, 4.5% in kidneys, 1.2% in spleen, 0.15% in adrenal glands, and trace amounts in bone marrow, eyes, lungs, and heart. Suborgan distribution of 14 C-FGF2 showed that for kidneys and adrenal glands, the labeling was mainly concentrated in the cortical zone. Incubation of organ sections with 2 M NaCl or heparin eluted all the radioactivity, indicating that labeling was due to FGF2-heparan sulfate proteoglycan (HSPG) interactions. Electrophoretic analysis show only native 14 C-FGF2 in the blood and extracellular matrix; however, FGF2 is continuously catabolized in solid organs, indicating that all participate in the clearance of FGF2 by cellular internalization and subsequent catabolism. All FGF2 catabolic fragments bound heparin, demonstrating the preservation of their HSPG-binding site during the in vivo intracellular catabolism of FGF2. Analysis of the high-affinity receptors of FGF2 (FGFR-1 and FGFR-3) and the mitogen-activated protein kinase did not show any increase in either FGFR tyrosine phosphorylation or in mitogen-activated protein kinase activation. This study shows for the first time that exogenous FGF2 is cleared by HSPG cellular internalization and catabolism without inducing the activation of FGFRs within at least five organs in vivo, which strongly suggests that the HSPG-dependent internalization and catabolism pathway may control the in vivo bioavailability of FGF2.

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Section: Hspg Regulates the Bioavailability Of Fgf2 In Vivo 79mentioning

confidence: 99%

In Vivo Involvement of Heparan Sulfate Proteoglycan in the Bioavailability, Internalization, and Catabolism of Exogenous Basic Fibroblast Growth Factor

et al. 1999

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“…Platelet derived growth factor R [104] cleavage I Fibroblast growth factor [105] Colony stimulating factor-1R (MCFR, c-fms) [106] cleavage ARK [107] cleavage Tie [108] cleavage Insulin R [109] intact Insulin-like growth factor-IIR (mannose 6-phosphate R) [110] extracellular space and subsequently activates intracellular signaling on binding to cell-associated receptor subunits. An expected outcome of this model is that soluble receptor-ligand complexes can confer ligand sensitivity to cells that express signaling receptor subunits but not the ligand-binding subunit.…”

Section: Mechanisms Of Soluble Receptor Actionmentioning

confidence: 99%

Soluble receptors in human disease

Heaney

Golde

1998

Journal of Leukocyte Biology

155

132

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“…51 At normal plasma concentrations of fibrinogen (7 M) and FGF-2 (up to 6 pM) nearly all FGF-2 should be bound to fibrinogen considering the dissociation constants (Kds) in the nanomolar range. 19 However, other FGF-2 binding proteins, ␣ 2 -macroglobulin 52 and soluble forms of FGFR, 53 have also been identified in blood. The binding of FGF-2 to ␣ 2 -macroglobulin involves formation of covalent bonds and is slow, requiring up to 4 hours to reach completion.…”

Section: Discussionmentioning

confidence: 99%

FGF-2 binding to fibrin(ogen) is required for augmented angiogenesis

Sahni

Khorana

Baggs

et al. 2006

Blood

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We have shown previously that fibrin(ogen) binds fibroblast growth factor 2 (FGF-2) and potentiates stimulation of endothelial-cell (EC) proliferation. We have now used 2 FGF-2 mutants differing only in the 5 residues constituting the binding site to characterize the importance of this interaction in angiogenesis. The nonbinding (2212) and binding (221*2) mutants stimulated EC proliferation by 2.2 ؎ 0.4-fold and 2.9 ؎ 0.3-fold over control, respectively, and both were similar to wild-type (wt) FGF-2 (2.5 ؎ 0.3-fold). Proliferation was augmented by fibrinogen to 5.3 ؎ 1.2-fold and 4.8 ؎ 0.8-fold with wtFGF-2 and 221*2, whereas no augmentation occurred with 2212 and fibrinogen. Using a placental explant model in a fibrin matrix, wtFGF-2 resulted in 2.6 ؎ 0.9-fold more growth over control, and 221*2 increased growth 3.3 plus or minus 0.9-fold. Vessel outgrowth with 2212 was minimal and comparable to control. Similarly, fibrinogen potentiated wtFGF-2 or 221*2-mediated angiogenesis in the chicken chorioallantoic membrane model. In a mouse Matrigel implant model, fibrinogen significantly increased angiogenesis with either wtFGF-2 or 221*2, whereas there was no augmentation with 2212. These results demonstrate that binding of FGF-2 to fibrin(ogen) mediated by the 5-residue FGF-2-fibrin(ogen) interactive site is required for augmented angiogenesis. ( IntroductionAngiogenesis is a complex process resulting in the development of new capillaries from pre-existing vessels and plays a critical role in a variety of pathologic conditions characterized by neovascularization including diabetic retinopathy, tumor growth, metastasis, and inflammatory diseases. 1 Angiogenesis is also one aspect of the response to injury that requires a coordinated interaction of the hemostatic and inflammatory systems and is regulated by cytokines and growth factors that act locally to regulate cellular proliferation and tissue repair. In this response, the activation of the hemostatic system results in platelet accumulation at the site of injury, and exposure of blood to tissue factor also leads to the formation of thrombin. Thrombin then cleaves fibrinopeptides from fibrinogen converting it to fibrin, which helps prevent blood loss and also serves as a temporary matrix to support tissue healing and remodeling. The role of fibrin in the cellular response is not passive as a structural matrix only, but rather it plays an active role through specific receptor-mediated interactions with cells of the blood and vessel wall. These result in fibrin-specific responses of endothelial cells (ECs) including adhesion and spreading, 2 proliferation, 3 protein synthesis, 4 and secretion. 5 Cytokines and growth factors are produced in response to injury and also act locally to modulate cell responses to vascular damage. Important among these are members of the fibroblast growth factor (FGF) family that exert a variety of effects on many cells and organ systems. 6 One member of this family, FGF-2, plays an important role in vascular responses by increasing EC pr...

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Identification of soluble forms of the fibroblast growth factor receptor in blood.

Abstract: We have purified three acidic (FGF-1) and basic (FGF-2) fibroblast growth factor binding proteins (FGF-BP1, FGF-BP2, and FGF-BP3) from human plasma and calf serum and demonstrate the presence of these circulating FGFBPs in blood. Each are truncated forms of the high-affinity

Cited by 83 publications

References 54 publications

In Vivo Involvement of Heparan Sulfate Proteoglycan in the Bioavailability, Internalization, and Catabolism of Exogenous Basic Fibroblast Growth Factor

In Vivo Involvement of Heparan Sulfate Proteoglycan in the Bioavailability, Internalization, and Catabolism of Exogenous Basic Fibroblast Growth Factor

Soluble receptors in human disease

FGF-2 binding to fibrin(ogen) is required for augmented angiogenesis

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