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.
Citations
More filters
TL;DR: In this article , the authors investigated FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to angiotensin II stimulation and found that blocking FGFR 1 suppresses Ang II-induced fibrogenic responses in epithelial cells.
Abstract: Background: Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. Methods: Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. Results: Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II–induced fibrogenic responses in epithelial cells. Mechanistically, Ang II–activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. Conclusions: Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.
5 citations
TL;DR: The results suggest that bFGF is very important for normal embryonic development and rat anti‐bFGF neutralizes bF GF effect.
Abstract: In this study, we aimed at the in vitro effects of anti-fibroblast growth factor-2 (anti-FGF-2 or anti-bFGF) on embryo culture in rats. In vitro effects of anti-bFGF on total embryonic development were investigated in 40 rat embryos (which were divided into four groups) (obtained from five pregnant females) at 9.5 days of gestation that were cultured in whole rat serum (WRS), and in WRS+ 2.5, 5, and 10 microg/ml anti-bFGF. After 48 h of culturing, the embryos from each group were harvested to be analysed morphologically according to a morphological scoring system and biochemically to obtain the embryo protein content. The morphological score, embryo protein content, somite number and crown-rump length of embryos indicated that embryos cultured in WRS+ anti-bFGF had significant embryonic retardation. Mean morphological scores for the embryos grown in WRS, in the presence of 2.5, 5 and 10 microg anti-FGF-2 were 61.4 +/- 1.64, 46.3 +/- 8.42, 27 +/- 2.58 and 13.6 +/- 0.96 respectively. These results suggest that bFGF is very important for normal embryonic development and rat anti-bFGF neutralizes bFGF effect.
5 citations
Cites background from "Fibroblast growth factors, their re..."
...FGFs produce their mitogenic and angiogenic activity in target cells by signalling through cell surface, tyrosine kinase receptors (Powers et al., 2000)....
[...]
01 Jan 2006
TL;DR: Two models are proposed, based on crystal structures, for the biological signaling complex of the FGFs, FGFRs, and the co-receptor heparin: these models show considerable differences that are of great importance to the mechanism of signaling, but nevertheless share common themes.
Abstract: Signaling by the fibroblast growth factors (FGFs) and their receptors (FGFRs) has been implicated in a wide range of diseases including cancer and arthritis. The need to understand the mechanisms of these diseases, and the potential for the development of novel therapeutics, has driven the characterization of complexes of the FGFs, FGFRs, and the co-receptor heparin. These efforts have led to the proposal of two models, based on crystal structures, for the biological signaling complex: these models show considerable differences that are of great importance to the mechanism of signaling, but nevertheless share common themes. The merits of these models have been illuminated by a range of further crystal structures that have revealed the more relevant conformations of each model. The development of methods in ultracentrifugation and mass spectrometry has allowed the analysis of both complexes in solution, and has suggested that both architectures bind only one molecule of heparin. New methods for sequencing heparin and preparing heparin derivatives have allowed the affinity of FGFs for heparins to be determined. Finally, evidence has accumulated for complexes involving more than two FGFRs, and tantalizing hints have emerged of how both crystallographic models may contribute to a larger “signalosome”.
5 citations
Journal Article•
TL;DR: It is concluded that RAS and FGFR3 mutations in UC are mutually exclusive and non-overlapping events which reflect activation of oncogenic pathways through different elements.
Abstract: Background: Urinary bladder cancer is a common malignancy in the West and ranks as the 7th most common cancer in our region of Kashmir, India. FGFR3 mutations are frequent in superficial urothelial carcinoma (UC) differing from the RAS gene mutational pattern. The aim of this study was to analyze the frequency and association of FGFR3 and RAS gene mutations in UC cases.
Materials and Methods: Paired tumor and adjacent normal tissue specimens of 65 consecutive UC patients were examined. DNA preparations were evaluated for the occurrence of FGFR3 and RAS gene mutations by PCR-SCCP and DNA sequencing.
Results: Somatic point mutations of FGFR3 were identified in 32.3% (21 of 65). The pattern and distribution were significantly associated with low grade/stage (p<0.05). The overall mutations in exon 1 and 2 in all the forms of RAS genes aggregated to 21.5% and showed no association with any clinic-pathological parameters. In total, 53.8% (35 of 65) of the tumors studied had mutations in either a RAS or FGFR3 gene, but these were totally mutually exclusive in and none of the samples showed both the mutational events in mutually exclusive RAS and FGFR3.
Conclusions: We conclude that RAS and FGFR3 mutations in UC are mutually exclusive and non-overlapping events which reflect activation of oncogenic pathways through different elements.
5 citations
Cites background from "Fibroblast growth factors, their re..."
...Fibroblast growth factor receptors regulate cell growth, differentiation, and angiogenesis (Hernandez et al., 2009, Powers et al., 2007)....
[...]
Dissertation•
24 Jun 2009
TL;DR: Nous avons cible notre etude sur le cancer du poumon, le plus frequent au niveau mondial tant en terme d'incidence que de mortalite, bien que paradoxalement, peu etudiee.
Abstract: Le cancer est un veritable probleme de sante publique et representera en 2010 la premiere cause de mortalite dans le monde. La lutte contre cette maladie est donc, plus que jamais, un enjeu capital. Les processus tumoraux associes a la carcinogenese, tels que la metastase, l'invasion ou l'angiogenese, dependent etroitement de la composition du milieu extracellulaire, lui-meme affecte par la secretion de proteines par les cellules tumorales. La mutation ou la variation d'expression de facteurs pro- ou anti-oncogenique joue un role important dans le developpement et la progression de la tumeur. Durant ce travail de these, nous avons voulu apporter des elements de reponse a la problematique suivante : l'etude par proteomique des proteines secretees par la tumeur apporte t'elle des informations contribuant a la comprehension des mecanismes de la tumorogenese et peut elle permettre de mettre en valeur de nouvelles cibles d'interet clinique ? Nous avons cible notre etude sur le cancer du poumon, le plus frequent au niveau mondial tant en terme d'incidence que de mortalite. Ce cancer presente le plus fort taux de mutation du gene p53, un anti-oncogene cle de la cellule. Cette perte de fonction module la secretion de nombreuses proteines dont l'investigation est primordiale, bien que paradoxalement, peu etudiee. Notre travail s'est ainsi focalise sur l'etude de l'influence de p53 sur la modulation de la secretion de proteines par les tumeurs du poumon. Nous avons ainsi developpe un procede d'analyse proteomique adapte, base notamment sur un marquage iTRAQ, une separation par isoelectrofocalisation de type OFFGEL et une analyse LC-MALDI-MS/MS. Ce procede a ete applique a l'etude du role joue par l'expression conditionnelle de p53 sur la modulation du secretome d'une lignee cellulaire d'adenocarcinome du cancer du poumon non a petites cellules. Plusieurs proteines d'interet ont ainsi ete caracterisees et confirmees in vivo chez la souris au niveau tumoral et plasmatique. Ces resultats apportent une meilleure comprehension du role primordial joue par l'alteration de p53 dans la modulation de l'environnement tumoral et font des secretomes cellulaires un modele de choix pour l'identification de marqueurs tumoraux.
5 citations
Cites background from "Fibroblast growth factors, their re..."
...L’interaction de FGF avec son récepteur conduit à une dimérisation et une autophosphorylation du récepteur, au recrutement d’adaptateurs cytosoliques tels que FRS2 (fibroblast growth factor receptor substrate 2) et à l’initiation de multiples voies de signalisation [297]....
[...]
References
More filters
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)....
[...]
...Phosphorylated tyrosine residues, in turn, recruit other signaling molecules to the activated receptors and propagate the signal through many possible transduction pathways (Pawson 1995)....
[...]
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…...
[...]
...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…...
[...]
...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)....
[...]
...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)....
[...]
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....
[...]