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: It is suggested that Betrofin3 modulates BDNF signaling with positive cardiomyogenic effect in stage and dose-dependent manner providing an effective strategy to increase ES cell-based generation ofCardiomyocytes and offer a novel therapeutic approach to cardiac pathologies where BDNF levels are impaired.
Abstract: Background/Aims: Pluripotent stem cells differentiating into cardiomyocyte-like cells in an appropriate cellular environment have attracted significant attention, given the potential use of such cells for regenerative medicine. However, the precise mechanisms of lineage specification of pluripotent stem cells are still largely to be explored. Identifying the role of various small synthetic peptides involved in cardiomyogenesis may provide new insights into pathways promoting cardiomyogenesis. Methods: In the present study, using a transgenic murine embryonic stem (ES) cell lineage expressing enhanced green fluorescent protein (EGFP) under the control of α-myosin heavy chain (α-MHC) promoter (pαMHC-EGFP), we investigated the cardiomyogenic effects of 7 synthetic peptides (Betrofin3, FGLs, FGLL, hNgf_C2, EnkaminE, Plannexin and C3) on cardiac differentiation. The expression of several cardiac-specific markers was determined by RT-PCR whereas the structural and functional properties of derived cardiomyocytes were examined by immunofluorescence and electrophysiology, respectively. Results: The results revealed that Betrofin3, an agonist of brain derived neurotrophic factor (BDNF) peptide exerted the most striking pro-cardiomyogenic effect on ES cells. We found that BDNF receptor, TrkB expression was up-regulated during differentiation. Treatment of differentiating cells with Betrofin3 between days 3 and 5 enhanced the expression of cardiac-specific markers and improved cardiomyocyte differentiation and functionality as revealed by genes regulation, flow cytometry and patch clamp analysis. Thus Betrofin3 may exert its cardiomyogenic effects on ES cells via TrkB receptor. Conclusion: Taken together, the results suggest that Betrofin3 modulates BDNF signaling with positive cardiomyogenic effect in stage and dose-dependent manner providing an effective strategy to increase ES cell-based generation of cardiomyocytes and offer a novel therapeutic approach to cardiac pathologies where BDNF levels are impaired.
10 citations
01 Jan 2006
TL;DR: The circulatory defects occur in both conducting vessels—which are prone to atherosclerosis—and the microcirculation, which shows signs of basement membrane thickening and diminished reparative capacity.
Abstract: Diabetes is on the rise in the United States and the rest of the world, and its complications are even more evident in the aging population Among the most severe complications of diabetes are impaired circulation and wound healing The former condition, together with peripheral neuropathy, contributes to an insensate, poorly vascularized lower extremity that is prone to the development of chronic wounds Lack of sensation leads to aggravation of the injury, which can frequently lead to the spread of infection and the loss of all or part of the lower limb The circulatory defects occur in both conducting vessels—which are prone to atherosclerosis—and the microcirculation, which shows signs of basement membrane thickening and diminished reparative capacity Surgical intervention can sometimes alleviate the macrovascular defects, but grafting procedures cannot guarantee that tissue perfusion can be restored With the exception of the retina, the poor growth of new capillary vessels in diabetes broadly diminishes the capacity to repair
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TL;DR: The expression of KGF and KGFR is differentially and significantly regulated in damaged liver tissue and might therefore not only contribute to morphological alterations but also regeneration of liver parenchyma most likely mediated by indirect mechanisms of action.
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TL;DR: Genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helping to complete the pathological molecular map of achONDroPLasia.
Abstract: Achondroplasia is a rare autosomal dominant genetic disease. Research on achondroplasia in China, however, has received little emphasis. Around 80–90% of cases of neonatal achondroplasia result from mutations in fibroblast growth factor receptor 3 (FGFR3) according to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Recently, genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helping to complete the pathological molecular map of achondroplasia. There are still, however, unknown aspects of the diagnosis and treatment of achondroplasia. This review will summarize advances in research on and the clinical diagnosis and treatment of achondroplasia in China.
10 citations
Cites background from "Fibroblast growth factors, their re..."
...Aberrant downstream signaling of ligand-receptor interaction of FGF3 and FGFR3 is also another key factor affecting achondroplasia (25)....
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01 Jan 2003
TL;DR: The study of the role of FGFs and FGFRs in pathologic conditions including developmental disorders and syndromes, angiogenic diseases, chronic inflammation, neurologic syndrome, hyperplastic, reactive diseases, and cancer, has greatly increased the knowledge of F GF actions, and led to the identification of new therapeutic molecular targets.
Abstract: This chapter reviews data showing that Fibroblast Growth Factors (FGF) are a family of related factors playing fundamental roles in several biological processes involving tissue remodeling such as embryonic development, angiogenesis, wound healing, nerve regeneration, chronic inflammation, and cancer. These processes are dependent on several biologic responses mediated by FGFs, including cell survival, proliferation, migration, invasion, and differentiation. The capability of FGFs to elicit many different responses through intracrine, autocrine, and paracrine actions confers a notable plasticity. FGFs also play a key role in hematopoiesis, and have neurotrophic properties. These studies have increased knowledge about the structure of both FGF, and FGFR proteins, their stability in vivo, the mechanisms of FGF production, export, import and cell trafficking, regulation of their functions by ECM molecules, the structure of FGFR in complex with their ligands, and the role and mechanisms of FGFR signaling in several biologic models. Recent studies have attempted to identify specific FGF signaling pathways underlying different responses. FGF-dependent cell migration appears to be preferentially dependent on Src and p38 MAP kinase activation, whereas cell proliferation is dependent on ERKs. The complexity of FGF mediated processes represents an extraordinary challenge to future research. The study of the role of FGFs and FGFRs in pathologic conditions including developmental disorders and syndromes, angiogenic diseases, chronic inflammation, neurologic syndromes, hyperplastic, reactive diseases, and cancer, has greatly increased the knowledge of FGF actions, and led to the identification of new therapeutic molecular targets.
10 citations
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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