Fibroblast growth factors, their receptors and signaling.
TL;DR: FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.
Abstract: Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.
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TL;DR: Researchers are now exploring the potential applications and uses of fibroblast growth factor in periodontal regeneration, including topical application of recombinant cytokines.
Abstract: Periodontitis is caused by bacterial biofilms and is modulated by a variety of risk factors. The periodontal ligament comprises heterogeneous cell populations which are lost in the disease process. A variety of regenerative therapies, such as bone grafts, guided tissue regeneration treatment, application of enamel matrix derivative, have been introduced, with some success in periodontal tissue regeneration. Topical application of recombinant cytokines is now one of the most effective methods to stimulate stem cells. Researchers are now exploring the potential applications and uses of fibroblast growth factor in periodontal regeneration.
10 citations
TL;DR: Results indicate that ATP oscillations mediate the actions of FGF and Shh signalling on prechondrogenic condensation, and proposes that morphogens organize skeletal patterns via ATP oscillation.
Abstract: Skeletal patterns are prefigured by prechondrogenic condensation. Morphogens such as fibroblast growth factor (FGF) and sonic hedgehog (Shh) specify the skeletal patterns in limb development. However, how morphogens regulate prechondrogenic condensation has remained unclear. Recently, it was demonstrated that synchronized Adenosine triphosphate (ATP) oscillations play a critical role in prechondrogenic condensation. Thus, the present study has focused on whether ATP oscillations mediate the actions of major developmental morphogens such as FGF and Shh on prechondrogenic condensation. It has been shown that both FGF and Shh signalling promoted cellular condensation but not chondrogenic differentiation and also induced ATP oscillations. In addition, blockage of FGF and Shh signalling prevented both ATP oscillations and prechondrogenic condensation. Furthermore, it was found that inhibition of ATP oscillations suppressed FGF/Shh-induced prechondrogenic condensation. These results indicate that ATP oscillations mediate the actions of FGF and Shh signalling on prechondrogenic condensation. This study proposes that morphogens organize skeletal patterns via ATP oscillations. Copyright © 2012 John Wiley & Sons, Ltd.
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TL;DR: The role of extracellular trophic factors and their receptor-mediated signaling pathways during cellular responses to oxidant stress is reemphasized and a first indication that the alternatively spliced FGFR-1 isoforms induce differential signal transduction pathways is provided.
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TL;DR: FGF-7 and FGFR2IIIb mRNA expression is regulated differently by exogenous ovarian steroids, assuming progesterone in connection with a specific amount of 17beta-estradiol, whereas the receptor seems to be inhibited by estradiol.
Abstract: The aim of this study was to characterize the effect of ovarian steroids and early gestation on the expression of fibroblast growth factor 7 (FGF-7) and its receptor (FGFR2IIIb) in the porcine endometrium. In Experiment 1, gilts were ovariectomized (OVX) on day 10 of the estrous cycle and treated thereafter with vehicle (VEH), progesterone (P4), estradiol benzoate (EB), or P4+EB. Days 12 and 20 cyclic gilts (C12 and C20) were used to determine the influence of physiologically low and high plasma estradiol and progesterone concentrations on their expression. In Experiment 2, the expression of FGF-7 and FGFR2IIIB was characterized on days 1 (G 1) and 12 (G 12) of gestation. FGF-7 and FGFR2IIIb mRNA were quantified by quantitative real-time RT-PCR, and localization of FGF-7 protein in steroid-treated and early pregnant gilts was performed by immunohistochemistry. VEH-gilts expressed both FGF-7 and FGFR2IIIB mRNA. We found a significant effect of EB, but no effects of P4 or P4+EB on the mRNA expression of FGF-7. FGFR2IIIb mRNA significantly decreased after the EB and combined P4+EB treatments, compared to P4 only substituted animals. Day 12 cyclic gilts showed significantly higher FGF-7 and FGFR2IIIb mRNA expression compared with day 20 gilts. Between day 1 and 12 of gestation, FGF-7 mRNA expression differed highly while FGFR2IIIb transcripts only varied significantly. FGF-7 protein was localized in endometrial epithelia, vascular smooth muscle, and the endothelium of different types of blood vessels. Staining was weak in VEH and P4 treated gilts, whereas it was prominent following EB and P4+EB. FGF-7 antibody strongly stained the luminal epithelium on day 12 of gestation. In summary, FGF-7 and FGFR2IIIb mRNA expression is regulated differently by exogenous ovarian steroids, assuming progesterone in connection with a specific amount of 17beta-estradiol, whereas the receptor seems to be inhibited by estradiol. Both transcripts coordinately increased during the progesterone dominated phase on day 12 both in cyclic and early pregnant gilts. We conclude that estradiol and progesterone are involved in the regulation of this ligand-receptor system, which might have an important role in preparing endometrial tissue for implantation in gilts.
10 citations
Cites background from "Fibroblast growth factors, their re..."
...attributed to the vascular endothelial growth factor (VEGF) [34], FGF-1, and FGF-2 [35]....
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...Angiogenic capabilities are mainly attributed to the vascular endothelial growth factor (VEGF) [34], FGF-1, and FGF-2 [35]....
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TL;DR: Enhanced cellular cholesterol stimulatesThrombin-induced release of FGF-2 and increases the mitogenic response toward thrombin in human SMCs, which might also be relevant for throm bin-induced mitogenesis in hypercholesterolemia in vivo.
Abstract: Objective— The mitogenic response to the G protein–coupled receptor agonist thrombin in human vascular smooth muscle cells (SMCs) depends on release of fibroblast growth factor-2 (FGF-2). Yet, intracellular mechanisms triggering FGF-2 release are unknown. The present study investigates possible effects of cholesterol enrichment and depletion, which have been shown to influence FGF-2–dependent signaling and SMC mitogenesis, on thrombin-induced FGF-2 release. Methods and Results— Cultured human aortic and saphenous vein SMCs were enriched with cholesterol by using a cyclodextrin-cholesterol complex. Cholesterol accumulation was determined by a fluorometric assay. ELISA, Western blotting, and RT-PCR were used for quantification of FGF-2 levels. DNA synthesis was determined by [ 3 H]-thymidine incorporation, proliferation by cell counting. Stimulation of SMCs with thrombin (30 nmol/L) resulted in release of FGF-2 into the pericellular space within 10 minutes. Preincubation with cyclodextrin-cholesterol caused accumulation of cellular cholesterol, increased thrombin-induced FGF-2 release, and stimulated FGF-2 de novo synthesis. Thrombin-induced DNA synthesis and proliferation were enhanced in cholesterol-rich SMCs. This effect was inhibited by FGF-2-neutralizing antibodies. Conclusions— Enhanced cellular cholesterol stimulates thrombin-induced release of FGF-2 and increases the mitogenic response toward thrombin in human SMCs. This mechanism might also be relevant for thrombin-induced mitogenesis in hypercholesterolemia in vivo.
10 citations
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TL;DR: It is demonstrated that free heparin and heparan sulfate can reconstitute a low affinity receptor that is, in turn, required for the high affinity binding of bFGF.
2,448 citations
TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"Fibroblast growth factors, their re..." refers background in this paper
...One way these recruited target proteins may be localized to the activated receptor is through the interaction between their Src-homology 2 (SH2) domains and specific phosphotyrosine residues on the activated receptor (Pawson 1995)....
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...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
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TL;DR: Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of Thalidomid-treated embryos.
Abstract: Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
2,364 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
"Fibroblast growth factors, their re..." refers background in this paper
...†From Ornitz et al. (1996), except where stated; ‡From Koga et al. (1995); §From Miralles et al. (1999); ¶From Xu et al. (1999). topologically identical to interleukin-1β (IL-1β) (Zhu et al. 1991), with which some members also share the feature of secretion by an endoplasmic reticulum…...
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...Mutation of all four cysteines to serines results in a protein with the same secondary structure and equally mitogenic for 3T3 cells as the wild-type FGF-2 (Foxet al. 1988), suggesting that the formation of disulfide bridges is not important for the secondary structure and mitogenic activity of…...
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...Ornitz et al. (1996) determined the specificity of different FGFs for different receptor isoforms by overexpressing these isoforms in Baf3 cells, which do not normally express FGFRs, and assaying for [3H]thymidine incorporation in these cells following treatment with different FGFs (see Table 2)....
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...1, IIIb 100 60 34 16 4 5 6 4 4 1, IIIc 100 104 0 102 59 55 0 1 21 2, IIIb 100 9 45 15 5 5 81 4 7 2, IIIc 100 64 4 94 25 61 2.5 16 89 3, IIIb 100 1 2 1 1 1 1 1 42 3, IIIc 100 107 1 69 12 9 1 41 96 4 100 113 6 108 7 79 2 76 75 Modified from Ornitz et al. (1996)....
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1,994 citations
"Fibroblast growth factors, their re..." refers background in this paper
...Defining features of the FGF family are a strong affinity for heparin and HLGAGs (Burgess & Maciag 1989), as well as a central core of 140 amino acids that is highly homologous between different family members....
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