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•

The role of fibroblast growth factor receptor 4 polymorphisms in the susceptibility and clinical features of ischemic stroke

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Changhao Yin, Siou Li, Weina Zhao, Yan-qin Guo, Ying Zhang, Jiachun Feng - Show less +2 more

01 Feb 2014-Journal of Clinical Neuroscience

TL;DR: A positive association between FGFR-4 gene polymorphism at rs351855G/A and susceptibility to ischemic stroke is suggested.

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3 citations

Posted Content•DOI•

FGF2 disruption enhances thermogenesis in brown and beige fat to protect against obesity and hepatic steatosis

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Haifang Li¹, Xinzhi Zhang¹, Cheng Huang¹, Huan Liu¹, Shuang Liu¹, Qiang Zhang¹, Mei Dong¹, Mengjie Hou¹, Yiming Liu¹, Hai Lin¹ - Show less +6 more•Institutions (1)

Shandong Agricultural University¹

02 Dec 2020-bioRxiv

TL;DR: FGF2 gene disruption resulted in increased thermogenic capability in both brown and beige fat, which was supported by increased UCP1 expression, enhanced respiratory exchange ratio, and elevated thermogenic potential under cold challenge or β-adrenergic stimulation.

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Abstract: Since brown and beige fat expend energy in the form of heat via non-shivering thermogenesis, identifying key regulators of thermogenic functions represents a major goal for development of potential therapeutic avenues for obesity and associated disorders. Here, we identified fibroblast growth factor 2 (FGF2) as a novel thermogenic regulator. FGF2 gene disruption resulted in increased thermogenic capability in both brown and beige fat, which was supported by increased UCP1 expression, enhanced respiratory exchange ratio, and elevated thermogenic potential under cold challenge or β-adrenergic stimulation. Thus, deletion of FGF2 protected mice from high fat-induced obesity and hepatic steatosis. Mechanistically, FGF2 acts in autocrine/paracrine fashions in vitro. Exogenous FGF2 supplementation inhibits both PGC-α and PPARγ; expression through ERK phosphorylation, thereby limiting PGC-1α/PPARγ interactions, and leading to suppression of UCP1 expression and thermogenic activity in brown and beige adipocytes. These findings suggest a viable potential strategy for use of FGF2-selective inhibitors in treatment of combating obesity and related disorders.

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3 citations

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

...Fibroblast growth factor 2 (FGF2), also known as basic FGF (bFGF), is among the first recognized members of the FGF family (Powers et al., 2000)....
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Journal Article•DOI•

Therapeutic Efficacy of Arnica in Hamsters with Cutaneous Leishmaniasis Caused by Leishmania braziliensis and L. tropica

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Sara M. Robledo, J. Murillo, Natalia Arbeláez, A. Montoya, Victoria Ospina, Franziska Jürgens, Iván D. Vélez, Thomas J. Schmidt - Show less +4 more

22 Jun 2022-Pharmaceuticals

TL;DR: The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica and results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL.

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Abstract: Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 μg/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 μg STL/2× day/60 d, 72.7% at doses of 19.2 μg STL/1× d/60 d and 67% at a dose of 38.4 μg STL/2× d/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 μg STL/2× day/60 d and 71% at a dose of 38.4 μg STL/2× d/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL.

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3 citations

The regulation of growth factor signaling in Drosophila development and disease

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Jonathan Ryan Lindner

01 Jan 2010

TL;DR: Trol is shown to be able to differentially regulate multiple signaling pathways during several developmental processes, including growth factor pathways during induction of a Drosophila prostate cancer model.

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Abstract: The Regulation of Growth Factor Signaling in Drosophila Development and Disease. (December 2010) Jonathan Ryan Lindner, B.S., University of Wisconsin Chair of Advisory Committee: Dr. Sumana Datta Developmental signaling pathways have many diverse roles throughout the life of an organism. The proper regulation of these pathways is essential for normal development, and misregulation can lead to diseases such as cancer. Heparan sulfate proteoglycans function to modulate growth factor signaling in many biological processes by acting as co-receptors, or by influencing ligand distribution. The heparan sulfate proteoglycan Trol, the Drosophila Perlecan homolog, is known to modulate signaling in a population of neuroblasts in the developing Drosophila central nervous system. My studies aim to determine the function Trol has in regulating signaling pathways during development. trol mutants are examined to determine how various mutant alleles impact signaling in several different developmental contexts. The role growth factor pathways play during induction of a Drosophila prostate cancer model is also examined. Gene expression profiles are determined for two types of prostate model overproliferation. Trol is shown to be able to differentially regulate multiple signaling pathways during several developmental processes. The Drosophila prostate cancer model is also shown

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2 citations

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

...Both of these pathways are active in the developing Drosophila eye disc and/or third instar brain along with Hh and Ras-MAPK signaling (Kaphingst et al., 1994; Silver and Rebay, 2005)....
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...A complex is then formed with Son of sevenless, which can initiate the RAS-RAF-MEKMAPK kinase cascade through GTP exchange with Ras (Tsang and Dawid, 2004; Groth and Lardelli, 2002; Powers et al., 2000)....
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...MAPK kinase cascade through GTP exchange with Ras (Tsang and Dawid, 2004; Groth and Lardelli, 2002; Powers et al., 2000)....
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...The hemocytes continue to respond to growth factor signaling cues, as activation of the Ras-MAPK pathway through expression of a constitutively active form of Ras leads to a 40-fold increase in cell numbers (Asha et al, 2003)....
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...It is interesting to note that we have connected Perlecan with FGF and Hh signaling in the developing fly brain while mouse studies have shown that Perlecan knock-out mice have cerebral cortex abnormalities (Costell et al., 1999; Park et al., 2003; Datta, 1995). trol mutant larvae have decreased numbers of circulating hemocytes that are likely due to decreased RasMAPK signaling by VEGF/PDGF. Perlecan knock-out mice also have defects in chondrogenesis and cardiovascular development and mammalian studies have demonstrated a role for Perlecan in angiogenesis driven by FGFs, VEGF and PDGF (Iozzo, 2005)....
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Book Chapter•DOI•

Signaling from Fibroblast Growth Factor Receptors in Development and Disease

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Kristine A. Drafahl¹, Christopher W. McAndrew¹, Daniel J. Donoghue¹•Institutions (1)

University of California, San Diego¹

01 Jan 2010

TL;DR: Fibroblast growth factor receptors constitute a family of four structurally related, cell surface receptor tyrosine kinases (RTKs), with 55–72% homology, and are essential for embryonic and neural development, skeletal and organ formation, and adult tissue homoeostasis.

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Abstract: Publisher Summary Fibroblast growth factor receptors (FGFRs) constitute a family of four (FGFR1–4) structurally related, cell surface receptor tyrosine kinases (RTKs), with 55–72% homology. FGFRs are involved in a variety of biological processes, including cell growth, migration, differentiation, survival, and apoptosis, and are essential for embryonic and neural development, skeletal and organ formation, and adult tissue homoeostasis. The three main signaling pathways associated with FGFR activation include the Ras/MAPK, PI 3-kinase, and PLCg pathways. All but one of the mutations known for the Fgfr genes are gain-of-function mutations, and activation of these receptors is associated with many developmental and skeletal disorders. Additionally, FGFR and FGF overexpression has been observed in many tumor samples, and mutations are also likely to be involved in carcinogenesis. Also, during embryonic development, FGFR signaling is essential for organ growth and patterning of the embryo. Activation of FGFRs can result in a variety of outcomes by initiating various intracellular signaling pathways. In many cases, the pathways activated depend on the cell type or stage of differentiation, leading to specific activation of downstream targets. Specific mutations in the Fgfr1–3 genes lead to congenital bone diseases classified as chondrodysplasia and craniosynostosis syndromes, which cause dwarfism, deafness, and abnormalities of the skeleton, skin, and eye. Finally, FGFRs and many of their ligands play roles in cancer progression by angiogenesis, changes in cell morphology, increased motility, and tumor cell proliferation.

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2 citations

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References

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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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