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: This study used a chick electroporation assay and in vitro mouse brain explant experiments to compare the activity of FGF17b and FGF18 to FGF8a and F GF8b, and found that FGF9b can transform the midbrain into a cerebellum fate, whereas FGF7a can promote midbrain development.
Abstract: Early patterning of the vertebrate midbrain and cerebellum is regulated by a mid/hindbrain organizer that produces three fibroblast growth factors (FGF8, FGF17 and FGF18). The mechanism by which each FGF contributes to patterning the midbrain, and induces a cerebellum in rhombomere 1 (r1) is not clear. We and others have found that FGF8b can transform the midbrain into a cerebellum fate, whereas FGF8a can promote midbrain development. In this study we used a chick electroporation assay and in vitro mouse brain explant experiments to compare the activity of FGF17b and FGF18 to FGF8a and FGF8b. First, FGF8b is the only protein that can induce the r1 gene Gbx2 and strongly activate the pathway inhibitors Spry1/2, as well as repress the midbrain gene Otx2 . Consistent with previous studies that indicated high level FGF signaling is required to induce these gene expression changes, electroporation of activated FGFRs produce similar gene expression changes to FGF8b. Second, FGF8b extends the organizer along the junction between the induced Gbx2 domain and the remaining Otx2 region in the midbrain, correlating with cerebellum development. By contrast, FGF17b and FGF18 mimic FGF8a by causing expansion of the midbrain and upregulating midbrain gene expression. This result is consistent with Fgf17 and Fgf18 being expressed in the midbrain and not just in r1 as Fgf8 is. Third, analysis of gene expression in mouse brain explants with beads soaked in FGF8b or FGF17b showed that the distinct activities of FGF17b and FGF8b are not due to differences in the amount of FGF17b protein produced in vivo. Finally, brain explants were used to define a positive feedback loop involving FGF8b mediated upregulation of Fgf18 , and two negative feedback loops that include repression of Fgfr2/3 and direct induction of Spry1/2 . As Fgf17 and Fgf18 are co-expressed with Fgf8 in many tissues, our studies have broad implications for how these FGFs differentially control development.
118 citations
Cites background from "Fibroblast growth factors, their re..."
...Furthermore, lossof-function studies in mouse and zebrafish have shown that Fgf8 is required for normal development of the midbrain and cerebellum (Meyers et al., 1998; Reifers et al., 1998; Chi et al., 2003)....
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TL;DR: Results confirm the established notion that FGFR2 IIIB ligands (FGF7 and FGF10) are important for wound healing and suggest that decreased expression of multiple FGF ligands contributes to the slowing of wound healing in aged mice and indicate the potential importance of further study of the involvement of FGF9, 16, 18 and 23 in the wound healing process.
Abstract: The highly ordered process of wound healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors. Consequently, the slowing of wound healing that occurs in the aged may be related to changes in the activity of these various regulatory factors. To gain additional insight into these issues, we quantified the absolute copy numbers of mRNAs encoding all the fibroblast growth factors (FGFs), their receptors (FGFRs) and two other growth factors in the dorsal skin of young and aged mice during the healing of full-thickness skin excisional wounds. In young adult mice (8 weeks old), FGF7, FGF10 and FGF22 mRNAs were all strongly expressed in healthy skin, and levels of FGF7 and 10 but not 22 increased 2- to 3.5-fold over differing time courses after wounding. The levels of FGF9, 16, 18 and especially 23 mRNAs were moderate or low in healthy skin but increased 2- to 33-fold after wounding. Among the four FGFRs, expression of only FGFR1 mRNA was augmented during wound healing. Expression of transforming growth factor-beta and hepatocyte growth factor was also high in healthy skin and was upregulated during healing. Notably, in aged mice (35 weeks old), where healing proceeded more slowly than in the young, both the basal and wound-induced mRNA expression of most of these genes was reduced. While these results confirm the established notion that FGFR2 IIIB ligands (FGF7 and FGF10) are important for wound healing, they also suggest that decreased expression of multiple FGF ligands contributes to the slowing of wound healing in aged mice and indicate the potential importance of further study of the involvement of FGF9, 16, 18 and 23 in the wound healing process.
117 citations
Cites background from "Fibroblast growth factors, their re..."
...In young adult mice (8 weeks old), FGF7, FGF10 and FGF22 mRNAs were all strongly expressed in healthy skin, and levels of FGF7 and 10 but not 22 increased 2- to 3·5-fold over differing time courses after wounding....
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...The levels of FGF9, 16, 18 and especially 23 mRNAs were moderate or low in healthy skin but increased 2- to 33-fold after wounding....
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TL;DR: Functional overlap of FGF8 and FGF10 signaling from second heart field mesoderm during development of the OFT/RV is shown, highlighting the sensitivity of these key aspects of cardiovascular development to FGF dosage.
Abstract: Rationale: The genes encoding fibroblast growth factor (FGF) 8 and 10 are expressed in the anterior part of the second heart field that constitutes a population of cardiac progenitor cells contributing to the arterial pole of the heart. Previous studies of hypomorphic and conditional Fgf8 mutants show disrupted outflow tract (OFT) and right ventricle (RV) development, whereas Fgf10 mutants do not have detectable OFT defects. Objectives: Our aim was to investigate functional overlap between Fgf8 and Fgf10 during formation of the arterial pole. Methods and Results: We generated mesodermal Fgf8; Fgf10 compound mutants with MesP1Cre . The OFT/RV morphology in these mutants was affected with variable penetrance; however, the incidence of embryos with severely affected OFT/RV morphology was significantly increased in response to decreasing Fgf8 and Fgf10 gene dosage. Fgf8 expression in the pharyngeal arch ectoderm is important for development of the pharyngeal arch arteries and their derivatives. We now show that Fgf8 deletion in the mesoderm alone leads to pharyngeal arch artery phenotypes and that these vascular phenotypes are exacerbated by loss of Fgf10 function in the mesodermal core of the arches. Conclusions: These results show functional overlap of FGF8 and FGF10 signaling from second heart field mesoderm during development of the OFT/RV, and from pharyngeal arch mesoderm during pharyngeal arch artery formation, highlighting the sensitivity of these key aspects of cardiovascular development to FGF dosage.
116 citations
TL;DR: Following receptor-mediated endocytosis, the exogenous FGF-2 can be transported to the nuclei of target cells, and this is of importance for the transmittance of a mitogenic signal.
Abstract: Regulation of the subcellular localization of certain proteins is a mechanism for the regulation of their biological activities. FGF-2 can be produced as distinct isoforms by alternative initiation of translation on a single mRNA and the isoforms are differently sorted in cells. High molecular weight FGF-2 isoforms are not secreted from the cell, but are transported to the nucleus where they regulate cell growth or behavior in an intracrine fashion. 18 kDa FGF-2 can be secreted to the extracellular medium where it acts as a conventional growth factor by binding to and activation of cell-surface receptors. Furthermore, following receptor-mediated endocytosis, the exogenous FGF-2 can be transported to the nuclei of target cells, and this is of importance for the transmittance of a mitogenic signal. The growth factor is able to interact with several intracellular proteins. Here, the mode of action and biological role of intracellular FGF-2 are discussed.
116 citations
TL;DR: This study suggests that FGFR4 Gly388Arg polymorphism may predict prognosis in lung adenocarcinoma.
Abstract: Purpose Fibroblast growth factor receptor 4 (FGFR4) is a member of a family of transmembrane receptors with ligand-induced tyrosine kinase activity. The Gly388Arg polymorphism in the FGFR4 gene was reported to modulate cancer cell migration in vitro and to be associated with breast, colon, and prostate cancer prognostic parameters. The purpose of this study was to investigate the involvement of the FGFR4 polymorphism in lung tumorigenesis. Patients and Methods A case-control study was performed including 274 patients with histologically confirmed lung adenocarcinomaand 401 healthy control subjects from general population. mRNA expression analysis was carried out in healthy lung of cancer patients. Results Patients with the Arg/Arg or Gly/Arg genotypecomparedto those with a Gly/Gly genotypehad an earlier age at cancer onset (median age, 60.2 v 63.4 years), higher proportion of poor clinical stage disease (hazard ratio [HR], 2.3; 95% CI, 1.4 to 3.9; P Z .002), of nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.2; P Z .027), or of short-term survivors (HR, 1.6; 95% CI, 1.1 to 2.3; P Z .008). In healthy lungs, FGFR4 did not show allele-specific expression and mRNA levels were not associated with genotype. Conclusion This study suggests that FGFR4 Gly388Arg polymorphism may predict prognosis in lung adenocarcinoma.
115 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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