Fibroblast growth factors, their receptors and signaling.

doi:10.1677/ERC.0.0070165

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Fibroblast growth factors, their receptors and signaling.

Journal Article•DOI•

Fibroblast growth factors, their receptors and signaling.

Ciaran Powers¹, S W McLeskey, Anton Wellstein¹•Institutions (1)

Georgetown University¹

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.

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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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Journal Article•DOI•

Fibroblast Growth Factor Receptors (FGFRs) in Human Sperm: Expression, Functionality and Involvement in Motility Regulation

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Lucía Saucedo¹, Gabriela N. Buffa¹, Marina Rosso¹, Tomás Guillardoy¹, Adrian Góngora¹, María José Munuce², Mónica H. Vazquez-Levin¹, Clara I. Marín-Briggiler¹ - Show less +4 more•Institutions (2)

Instituto de Biología y Medicina Experimental¹, National University of Rosario²

13 May 2015-PLOS ONE

TL;DR: This study describes for the first time the presence, localization and functionality of human sperm FGFRs, and provides evidence of the beneficial effect of FGF2 upon sperm motility.

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Abstract: Fibroblast growth factors receptors (FGFRs) have been widely characterized in somatic cells, but there is scarce evidence of their expression and function in mammalian gametes. The objective of the present study was to evaluate the expression of FGFRs in human male germ cells, to determine sperm FGFR activation by the FGF2 ligand and their participation in the regulation of sperm motility. The expression of FGFR1, 2, 3 and 4 mRNAs and proteins in human testis and localization of these receptors in germ cells of the seminiferous epithelium was demonstrated. In ejaculated sperm, FGFRs were localized to the acrosomal region and flagellum. Sperm exposure to FGF2 caused an increase in flagellar FGFR phosphorylation and activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB or Akt) signaling pathways. Incubation with FGF2 led to a significant increase in the percentage of total and progressive sperm motility, as well as in sperm kinematics. All responses were prevented by sperm preincubation with BGJ398, a specific inhibitor of FGFR tyrosine kinase activity. In addition to confirming the expression of FGFRs in germ cells of the human testis, our study describes for the first time the presence, localization and functionality of human sperm FGFRs, and provides evidence of the beneficial effect of FGF2 upon sperm motility.

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39 citations

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

...domains of FGFR1, FGFR2 and FGFR3 are subjected to alternative splicing, giving rise to 2 or 3 receptor isoforms (IIIa, IIIb and IIIc) with specific tissue expression and different ligand binding properties [5]....
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Journal Article•DOI•

Know thy Sef: a novel class of feedback antagonists of receptor tyrosine kinase signaling.

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Dina Ron¹, Yaron Fuchs¹, Dror S. Chorev¹•Institutions (1)

Technion – Israel Institute of Technology¹

01 Jan 2008-The International Journal of Biochemistry & Cell Biology

TL;DR: Sef proteins represent a new class of feedback antagonists capable of regulating receptor tyrosine kinase signaling, and their involvement in development, as well as in other biological processes, was demonstrated by biochemical and genetic approaches.

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39 citations

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

...FGF ignal via four distinct high-affinity cell-surface tyrosine inase receptors, designated FGF receptors 1–4 (FGFR1– GFR4) (Powers et al., 2000)....
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Journal Article•DOI•

Expression of fibroblast growth factors (Fgfs) in murine tooth development

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Thantrira Porntaveetus¹, Yoko Otsuka-Tanaka¹, M. Albert Basson¹, Anne M. Moon², Paul T. Sharpe¹, Atsushi Ohazama¹ - Show less +2 more•Institutions (2)

King's College London¹, University of Utah²

01 May 2011-Journal of Anatomy

TL;DR: Comparison in situ hybridisation analysis of unexamined Fgf ligands during tooth development showed dynamic temporo‐spatial expression in murine tooth development, indicating likely functional redundancy in tooth development.

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Abstract: Fgf signalling is known to play critical roles in tooth development. Twenty-two Fgf ligands have been identified in mammals, but expression of only 10 in molars and three in the incisor loop stem cell region have been documented in murine tooth development. Our understanding of Fgf signalling in tooth development thus remains incomplete and we therefore carried out comparative in situ hybridisation analysis of unexamined Fgf ligands (eight in molars and 15 in cervical loops of incisors; Fgf11–Fgf14 were excluded from this analysis because they are not secreted and do not activate Fgf receptors) during tooth development. To identify where Fgf signalling is activated, we also examined the expression of Etv4 and Etv5, considered to be transcriptional targets of the Fgf signalling pathway. In molar tooth development, the expression of Fgf15 and Fgf20 was restricted to the primary enamel knots, whereas Etv4 and Etv5 were expressed in cells surrounding the primary enamel knots. Fgf20 expression was observed in the secondary enamel knots, whereas Fgf15 showed localised expression in the adjacent mesenchyme. Fgf16, Etv4 and Etv5 were strongly expressed in the ameloblasts of molars. In the incisor cervical loop stem cell region, Fgf17, Fgf18, Etv4 and Etv5 showed a restricted expression pattern. These molecules thus show dynamic temporo-spatial expression in murine tooth development. We also analysed teeth in Fgf15−/− and Fgf15−/−;Fgf8+/− mutant mice. Neither mutant showed significant abnormalities in tooth development, indicating likely functional redundancy.

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38 citations

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

...The members of the Fgf11 subfamily (Fgf11–Fgf14) were excluded from this analysis because they are not secreted and do not activate Fgf receptors, but instead are localised to the cell nucleus and have intracellular function (Powers et al. 2000; Zhang et al. 2006; Mason, 2007)....
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...Fgf signalling is transduced through a family of four transmembrane receptor tyrosine kinases in all vertebrates (Powers et al. 2000; Mason, 2007)....
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...Fgf signalling is transduced through a family of four transmembrane receptor tyrosine kinases in all vertebrates (Powers et al. 2000; Mason, 2007)....
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...Fibroblast growth factor (Fgf) signalling has been shown to play essential roles in regulating many biological processes including mitogenic, chemotactic and angiogenic activity and wound healing (Powers et al. 2000; Nie et al. 2006; Mason, 2007)....
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Journal Article•DOI•

Multi-tissue microarray analysis identifies a molecular signature of regeneration.

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Sarah E. Mercer¹, Chia-Ho Cheng², Donald L. Atkinson³, Jennifer Krcmery¹, Claudia E. Guzman¹, David T. Kent³, Katherine Zukor³, Kenneth A. Marx², Shannon J. Odelberg³, Hans Georg Simon¹ - Show less +6 more•Institutions (3)

Northwestern University¹, University of Massachusetts Lowell², University of Utah³

26 Dec 2012-PLOS ONE

TL;DR: A molecular signature for regeneration is established that consists of common genes or gene family members that exhibit dynamic differential regulation during regeneration in multiple tissue types that include members of the matrix metalloproteinase family and its regulators, extracellular matrix components, genes involved in controlling cytoskeleton dynamics, and a variety of immune response factors.

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Abstract: The inability to functionally repair tissues that are lost as a consequence of disease or injury remains a significant challenge for regenerative medicine. The molecular and cellular processes involved in complete restoration of tissue architecture and function are expected to be complex and remain largely unknown. Unlike humans, certain salamanders can completely regenerate injured tissues and lost appendages without scar formation. A parsimonious hypothesis would predict that all of these regenerative activities are regulated, at least in part, by a common set of genes. To test this hypothesis and identify genes that might control conserved regenerative processes, we performed a comprehensive microarray analysis of the early regenerative response in five regeneration-competent tissues from the newt Notophthalmus viridescens. Consistent with this hypothesis, we established a molecular signature for regeneration that consists of common genes or gene family members that exhibit dynamic differential regulation during regeneration in multiple tissue types. These genes include members of the matrix metalloproteinase family and its regulators, extracellular matrix components, genes involved in controlling cytoskeleton dynamics, and a variety of immune response factors. Gene Ontology term enrichment analysis validated and supported their functional activities in conserved regenerative processes. Surprisingly, dendrogram clustering and RadViz classification also revealed that each regenerative tissue had its own unique temporal expression profile, pointing to an inherent tissue-specific regenerative gene program. These new findings demand a reconsideration of how we conceptualize regenerative processes and how we devise new strategies for regenerative medicine.

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38 citations

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

...However, as FGFs are secreted into the extracellular environment, where they typically bind to heparan sulphate proteoglycans, the ECM essentially becomes a local reservoir for FGF signaling [71]....
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Journal Article•DOI•

Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

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Feng Liu¹, Shougang Zhuang¹, Shougang Zhuang²•Institutions (2)

Tongji University¹, Brown University²

20 Jun 2016-International Journal of Molecular Sciences

TL;DR: The evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal Fibrosis are summarized.

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Abstract: Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs) regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs) have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.

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38 citations

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

...FGFs act through binding to high-affinity FGFR, encoded by four genes that, through alternative mRNA splicing, can generate seven functional FGFR variants [46]....
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Journal Article•DOI•

Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor.

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Avner Yayon¹, Michael Klagsbrun², Jeffrey D. Esko³, Philip Leder⁴, David M. Ornitz⁴ - Show less +1 more•Institutions (4)

Weizmann Institute of Science¹, Harvard University², University of Alabama at Birmingham³, Howard Hughes Medical Institute⁴

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.

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2,448 citations

Journal Article•DOI•

Protein modules and signalling networks

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Tony Pawson¹•Institutions (1)

Mount Sinai Hospital, Toronto¹

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.

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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.

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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 Article•DOI•

Thalidomide is an inhibitor of angiogenesis.

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Robert J. D'Amato¹, Michael S. Loughnan, Evelyn Flynn, Judah Folkman•Institutions (1)

Harvard University¹

26 Apr 1994-Proceedings of the National Academy of Sciences of the United States of America

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.

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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.

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2,364 citations

Journal Article•DOI•

Receptor specificity of the fibroblast growth factor family.

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David M. Ornitz¹, Jingsong Xu¹, Jennifer S. Colvin¹, Donald G. McEwen¹, Craig A. MacArthur¹, François Coulier², Guangxia Gao³, Mitchell Goldfarb⁴ - Show less +4 more•Institutions (4)

Washington University in St. Louis¹, French Institute of Health and Medical Research², Columbia University³, Icahn School of Medicine at Mount Sinai⁴

21 Jun 1996-Journal of Biological Chemistry

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.

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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 Article•DOI•

The heparin-binding (fibroblast) growth factor family of proteins.

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Wilson H. Burgess, Thomas Maciag

01 Jan 1989-Annual Review of Biochemistry

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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