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: Conditional inactivation of fgfr 1 caused different phenotypes displaying in different cells or specific organs and revealed some novel functions of FGFR1 in bone development that facilitate the investigation on the underlying mechanism of the diseases.
Abstract: Accumulating data suggest that FGFs/FGFR1 plays essential roles in the bone development and human skeletal diseases. Conditional inactivation of fgfr 1 caused different phenotypes displaying in different cells or specific organs and revealed some novel functions of FGFR1 in bone development. Fgfr 1 mutation mainly induced 2 types of human skeletal diseases, craniosynostosis syndrome and dysplasias. Similar mutation of fgfr 1 in mouse model just mimicked the phenotype that happened in human. These facilitate the investigation on the underlying mechanism of the diseases. Here we mainly focused on the advance of FGFR1 function in the bone development and its mutation caused skeletal diseases.
1 citations
Patent•
18 Oct 2004
TL;DR: In this paper, an antibody or fragments thereof that are specific for a fibroblast growth factor receptor (FGFR)-1(IIIb), FGFR-1/IIIc, and/or FGFR/FGFR-4 was presented.
Abstract: The present invention is directed to an antibody or fragments thereof that are specific for a fibroblast growth factor receptor (FGFR)-1(IIIb), FGFR-1(IIIc), and/or FGFR-4. Also, provided herein, are vectors and host cells comprising the nucleic acids encoding those antibodies. The present invention further provides methods of antagonizing FGFR-1 or FGFR-4 as a treatment for obesity, diabetes, or a condition related thereto, and methods of reducing food intake.
1 citations
01 Jan 2012
1 citations
Dissertation•
01 Jan 2008
TL;DR: In this article, a large-scale microarray study was performed that provided insights into the global gene expression changes occurring in both wild-type (normal) and FGF/FGFR signalling deficient EBs, which resulted in an extensive catalogues of significantly expressed genes in both cell lines.
Abstract: Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of blastocyst stage embryos, and upon differentiation into embryoid bodies (EBs) they recapitulate the genetic, cellular and morphological events occurring in early embryogenesis. Among several signalling pathways and inductive factors, the fibroblast growth factors (FGFs) and their receptors (FGFRs) have been shown to be important during early embryogenesis. Previously it has been shown that ESCs expressing a mutant form of FGFR failed to form the two characteristic cell layers of EBs: the endoderm and the ectoderm. In addition, due to the impaired FGF/FGFR signalling, the mutant EBs failed to synthesize laminin-111 and collagen type IV, the main building blocks of the basement membrane (BM) protein network. The aim of this thesis was to elucidate the molecular and biological changes occurring due to impaired FGF/FGFR signalling in differentiating EBs. A large scale microarray study was performed that provided insights into the global gene expression changes occurring in both wild-type (normal) and FGF/FGFR signalling deficient EBs, which resulted in an extensive catalogues of significantly expressed genes in both cell lines. Results showed that during wild-type EB differentiation a rapid down-regulation of pluripotency related genes and up-regulation of genes related to morphogenesis and development occurred. Analysis of FGF/FGFR deficient EBs showed a significant decrease of genes encoding endodermal and BM related proteins. In addition, an increase of mesodermal and pluripotency related gene transcripts was observed. Such transcripts are normally activated later during EB development. The assumption was that the most significantly decreased genes could be involved in FGF/FGFR signalling. To further test this theory, we chose to elucidate the expression pattern of the hitherto uncharacterized gene 1110032E23Rik whose expression was significantly decreased in FGF/FGFR mutant EBs. By in situ hybridization analysis, the expression of 1110032E23Rik was examined in both mouse and Xenopus laevis (frog) embryonic development. Results showed that the expression of 1110032E23Rik in mouse embryos was restricted to epithelia such as the lining of the gastrointestinal tract, urogenital tract, heart, skin and lens, and in addition to the peripheral nervous tissues. Expression analysis of the mouse 1110032E23Rik orthologue in frog embryos showed that mice and frogs share several expression domains such as the eye, heart, kidney and epidermis. The expression was observed at locations where active FGF/FGFR signalling takes place and BMs are present. Based on the expression pattern observed in mice, we named this uncharacterized gene Ened (Expressed in Nerve and Epithelium during Development). (Less)
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References
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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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