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Journal ArticleDOI

Fibroblast growth factors, their receptors and signaling.

01 Sep 2000-Endocrine-related Cancer (Bioscientifica Ltd)-Vol. 7, Iss: 3, pp 165-197
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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Citations
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Journal ArticleDOI
TL;DR: Considering the possibility that Fgf19 plays a similar role in humans and chicks, this finding could explain the significant diencephalic phenotypic differences between humans and mice in models and diseases where the Shh pathway is affected.
Abstract: Fibroblast growth factors (Fgfs) constitute a family of signaling molecules that play essential roles in development. We have studied the expression pattern of mouse Fgf15 in the developing brain. Fgf19 is another member of the FGF family that has been suggested as the chick and human ortholog of mouse and rat Fgf15. Here, we compare the expression pattern during neural development of chick Fgf19 with mouse Fgf15. Unlike Fgf15, Fgf19 presents an expression in the isthmic alar plate, diencephalic and mesencephalic parabasal plates, hindbrain basal plate, as well as in the zona limitans intrathalamica (zli). Moreover, we explored the regulation between Fgf19 and the signaling molecules of the isthmic and zli organizers: Fgf8 and Shh, respectively. Considering the possibility that Fgf19 plays a similar role in humans and chicks, this finding could explain the significant diencephalic phenotypic differences between humans and mice in models and diseases where the Shh pathway is affected.

42 citations


Cites background from "Fibroblast growth factors, their re..."

  • ...Fgfs interact with Fgf-tyrosine-kinase receptors (FgfR) to mediate the regulation of cell proliferation, migration, survival, differentiation, growth, and cell identity (Goldfarb, 1996; Ornitz et al., 1996; Powers et al., 2000)....

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  • ...The roles of some Fgf proteins in development have been previously analyzed (for a review, see Powers et al., 2000)....

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  • ...© 2007 Wiley-Liss, Inc. they present mitogenic and angiogenic effects in cancer progression and active migratory effects in metastasis (reviewed in Goldfarb, 1996; Powers et al., 2000; Ornitz and Itoh, 2001)....

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Journal ArticleDOI
TL;DR: This review will attempt to summarize the main angiogenic growth factors involved in these physiological processes leading to angiogenesis and possible new mechanisms that could lead to this vascular regrowth.
Abstract: The formation of new blood vessels from existing ones is a major process of angiogenesis and it is most effective in the vascular systems. The physiological process like hypoxia inducible factors involved in the regeneration of damaged tissues varies within the vascular systems in the endothelium and could be limited due to some major angiogenic growth factors like vascular endothelial growth factor, fibroblast growth factors and epidermal growth factor among others which bring about this cellular vascular regrowth. These physiological processes leading to cellular vascular regrowth could be a major function for the treatment of cardiovascular diseases such as ischemia and atherosclerosis. Estrogens are one of the known factors within the cellular mechanisms that could initiate repairs to the damaged vascular tissues, since estrogens are known inducers of angiogenesis leading to this cellular regrowth. Research has also shown that this cellular regrowth is induced by vascular angiogenic growth factors via the estrogen receptors. In this review we will attempt to summarize the main angiogenic growth factors involved in these physiological processes leading to angiogenesis and possible new mechanisms that could lead to this vascular regrowth. And also we will try to summarize some reports on the effect of estrogen on these physiological processes leading to angiogenesis in cardiovascular diseases.

42 citations

Journal ArticleDOI
TL;DR: The results suggest that bFGF increased Fn expression in rat osteoblasts via the FGFR2/PLCγ2/ PKCα/c‐Src/NF‐κB signaling pathway.
Abstract: Fibronectin (Fn) is involved in early stages of bone formation and basic fibroblast growth factor (bFGF) is an important factor regulating osteogenesis. bFGF increased Fn expression, which was attenuated by phosphatidylinositol phospholipase inhibitor (U73122), protein kinase C inhibitor (GF109203X), Src inhibitor (PP2), NF-kappaB inhibitor (PDTC), IkappaBalpha phosphorylation inhibitor (Bay 117082), or IkappaB protease inhibitor (TPCK). bFGF-induced increase of Fn-luciferase activity was antagonized by cells transfected with Fn construct without NF-kappaB regulatory site. Stimulation of osteoblasts with bFGF activated IkappaB kinase alpha/beta (IKK alpha/beta) and increased IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-kappaB-specific DNA-protein complex and kappaB-luciferase activity. bFGF-mediated an increase of IKKalpha/beta activity and DNA-binding activity was inhibited by U73122, GF109203X, or PP2. The binding of p65 to the NF-kappaB element, as well as the recruitment of p300 and the enhancement of p50 acetylation on the Fn promoter was enhanced by bFGF. Overexpression of constitutively active FGF receptor 2 (FGFR2) increased Fn-luciferase activity, which was inhibited by co-transfection with dominant negative (DN) mutants of PLCgamma2, PKCalpha, c-Src, IKKalpha, or IKKbeta. Our results suggest that bFGF increased Fn expression in rat osteoblasts via the FGFR2/PLCgamma2/PKCalpha/c-Src/NF-kappaB signaling pathway.

42 citations


Cites background from "Fibroblast growth factors, their re..."

  • ...Binding of bFGF to its receptor results in autophosphorylation of the receptor (Powers et al., 2000), activation, and ultimately the induction of transcription regulatory proteins (Debiais et al., 2001; Kim et al., 2003). bFGF is a constituent of the bone matrix and cultured osteoblasts produce…...

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  • ...The cellular actions of FGFs are known to be mediated by interaction with FGFRs, a family of tyrosine kinase receptors (Powers et al., 2000)....

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Journal ArticleDOI
TL;DR: It is demonstrated that, although multiple FGFRs are induced in neointimal SMCs following arterial injury, specific interactions between distinctly spliced FGFR-2 isoforms and FGF-9 contribute to the proliferation of these SMCs.

42 citations

Journal ArticleDOI
01 Dec 2007-Obesity
TL;DR: Developing an improved culture system that allows the proliferation of human preadipocytes without loss of differentiation capacity is developed.
Abstract: Objective: The study of human preadipocytes is hampered by the limited availability of adipose tissue and low yield of cell preparation. Proliferation of preadipocytes using common protocols, including fetal bovine serum (FBS), results in a markedly reduced differentiation capacity. Therefore, we were interested in developing an improved culture system that allows the proliferation of human preadipocytes without loss of differentiation capacity. Research Methods and Procedures: Adipose tissue samples were taken from subjects undergoing elective abdominal surgery. Cells were seeded at various densities and cultured using different formulations of proliferation media including factors such as fibroblast growth factor-2 (basic fibroblast growth factor), epidermal growth factor, insulin, and FBS either alone or in combination. Cells were counted and induced to differentiate after confluence. After complete differentiation, cells were harvested, and glycerol-3-phosphate dehydrogenase activity was measured. Cells were subcultured for up to five passages. Results: The proliferation medium with 4 growth factors (PM4), consisting of 2.5% FBS, 10 ng/mL epidermal growth factor, 1 ng/mL basic fibroblast growth factor, and 8.7 µM insulin, resulted in lower doubling times at all seeding densities tested (0.05 × 104 to 1.5 × 104) compared with medium supplemented with 10% FBS. In contrast to cells in FBS medium, cells grown with PM4 medium retained full differentiation rate (glycerol-3-phosphate dehydrogenase activity, 493 ± 215 vs. 41 ± 17 mU/mg, p < 0.01). Differentiation capacity was fully retained at least for up to three passages in PM4 medium. Discussion: The use of PM4 medium results in substantial proliferation of human preadipocytes with preserved differentiation capacity. This novel technique represents a valuable tool for the study of human adipose tissue development and function starting from small samples.

42 citations


Cites background from "Fibroblast growth factors, their re..."

  • ...Both factors signal by membrane-associated receptors and share common mitogenic pathways including phospholipase C- and consecutive activation of protein kinase C (17,18)....

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References
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Journal ArticleDOI
22 Feb 1991-Cell
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

Journal ArticleDOI
16 Feb 1995-Nature
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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Journal ArticleDOI
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

Journal ArticleDOI
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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Journal ArticleDOI

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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