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•

Inhibition of fibroblast growth factor receptor 1: influence on tympanic membrane wound healing in rats

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Holger Kaftan¹, Lars Reuther¹, Bärbel Miehe¹, Werner Hosemann¹, Achim G. Beule¹ - Show less +1 more•Institutions (1)

University of Greifswald¹

01 Jan 2012-European Archives of Oto-rhino-laryngology

TL;DR: Fibroblast growth factor receptor 1 inhibition is a strong inhibitor of TM healing but seems not to be suitable to create a chronic TM perforation in rat, and differences in the histologic parameters between both groups are observed.

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Abstract: An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting healing of TM perforations. The basic fibroblast growth factor is important in TM wound healing. The object of this study was to investigate the efficacy of fibroblast growth factor receptor 1 (FGFR1) inhibition to arrest wound healing of experimental TM perforation. Bilateral instrumental myringotomies were performed in 12 rats. A specific inhibitor of the FGFR1 tyrosine kinase (SU5402) was applied to the left TM (2 mg/ml) and to the right TM (10 mg/ml) of each animal daily for 12 consecutive days. Thereafter, TMs were observed weekly for a total of 30 days. TM healing was delayed in a dose-dependent manner. We observed differences in the histologic parameters between both groups. SU 5402 is a strong inhibitor of TM healing but seems not to be suitable to create a chronic TM perforation in rat.

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17 citations

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

...FGFRs work much like the epidermal growth factor receptor (EGFR), which is also a tyrosine kinase transmembrane protein [23]....
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Journal Article•DOI•

Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway.

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Jing Yang¹, Dan Zhang¹, Ying Yu¹, Run-Ju Zhang¹, Xiao-Ling Hu¹, He-Feng Huang¹, Yong-Chao Lu¹ - Show less +3 more•Institutions (1)

Zhejiang University¹

17 Sep 2015-Cell Cycle

TL;DR: It is demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts.

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Abstract: Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation.

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17 citations

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

...The FGFs affect target cells via the activation of cell-surface tyrosine kinase receptors that are encoded by 4 genes in mammals (designated fgf1/2/3/4).(16,17) Evidence has shown that FGFs play important roles in the regulation of pluripotency and lineage segregation in both the early mouse embryo and pluripotent mammalian stem cells....
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...Besides, some researchers observed that the expression of FGF4 polypeptide as well as mRNA was limited to the ICM cells in the blastocyst.(17,20) One of central interest is FGF2, which is produced by luminal and glandular epithelium and is detectable in the uterine lumen throughout early pregnancy in animals....
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Journal Article•DOI•

Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma.

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Sandrine Siffroi-Fernandez¹, Ayca Cinaroglu, Véronique Fuhrmann-Panfalone, Guy Normand, Kuyas Bugra, José-Alain Sahel, David Hicks - Show less +3 more•Institutions (1)

French Institute of Health and Medical Research¹

01 Mar 2005-Archives of Ophthalmology

TL;DR: Y79 retinoblastoma expresses all 4 FGFRs, but FGFR1 activation entirely accounts for FGF-1-driven cell proliferation, and may contribute to developing therapeutic strategies to limit retinOBlastoma growth.

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Abstract: Objectives Fibroblast growth factors (FGFs) represent potent effectors and play essential roles in both normal development and many pathological processes. Little is known about their possible implication in retinoblastoma growth. We sought to examine FGF high- and low-affinity receptor (FGFR) expression, activation of FGFR1 by acidic FGF (FGF-1), and proliferative effects on Y79 cells. Methods Expression of FGFR1 to FGFR4 was screened in Y79 cells by means of immunochemical and reverse transcriptase polymerase chain reaction techniques. Tyrosine phosphorylation of FGFR1 induced by FGF was examined by immunoprecipitation after stimulation with FGF-1 in the presence or absence of heparin. Retinoblastoma proliferation was monitored by radiolabeled thymidine incorporation or a vital dye–based assay, after addition of FGF-1 with or without inclusion of a specific FGFR1 neutralizing antibody or FGFR1 antisense oligonucleotides. Low-affinity heparan sulfate proteoglycan coreceptors were blocked through sodium chlorate or heparinase treatment of Y79 cells. Results Y79 retinoblastoma expressed all 4 FGFRs, at both the protein and messenger RNA levels. The FGFR1 was differentially phosphorylated in a time- and heparin-dependent manner by FGF-1. Proliferation of Y79 cells induced by FGF-1 was entirely mediated by FGFR1, since inclusion of specific neutralizing antibodies or antisense oligonucleotides completely prevented tumor cell multiplication. Finally, FGF-1–induced proliferation was dependent on the presence and sulfation of heparan sulfate proteoglycan. Conclusions Y79 retinoblastoma expresses all 4 FGFRs, but FGFR1 activation entirely accounts for FGF-1–driven cell proliferation. Clinical Relevance These studies demonstrate a role for the FGF-1/FGFR1 pathway in retinoblastoma proliferation, and may contribute to developing therapeutic strategies to limit retinoblastoma growth.

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17 citations

Journal Article•DOI•

C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis.

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Zhuo Chen¹, Linjiang Tong¹, Bai-you Tang¹, Hongyan Liu¹, Xin Wang², Tao Zhang¹, Xianwen Cao², Yi Chen¹, Honglin Li², Xuhong Qian², Yufang Xu², Hua Xie¹, Jian Ding¹ - Show less +9 more•Institutions (2)

Chinese Academy of Sciences¹, East China University of Science and Technology²

01 Jun 2019-Acta Pharmacologica Sinica

TL;DR: C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.

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Abstract: The fibroblast growth factor receptors (FGFRs) are increasingly considered attractive targets for therapeutic cancer intervention due to their roles in tumor metastasis and angiogenesis. Here, we identified a new selective FGFR inhibitor, C11, and assessed its antitumor activities. C11 was a selective FGFR1 inhibitor with an IC50 of 19 nM among a panel of 20 tyrosine kinases. C11 inhibited cell proliferation in various tumors, particularly bladder cancer and breast cancer. C11 also inhibited breast cancer MDA-MB-231 cell migration and invasion via suppression of FGFR1 phosphorylation and its downstream signaling pathway. Suppression of matrix metalloproteinases 2/9 (MMP2/9) was associated with the anti-motility activity of C11. Furthermore, the anti-angiogenesis activity of C11 was verified in endothelial cells and chicken chorioallantoic membranes (CAMs). C11 inhibited the migration and tube formation of HMEC-1 endothelial cells and inhibited angiogenesis in a CAM assay. In sum, C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.

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17 citations

Journal Article•DOI•

Fibroblast growth factor 10 represses premature cell differentiation during establishment of the intestinal progenitor niche.

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Pia Nyeng¹, Maureen A. Bjerke¹, Gitte Anker Norgaard¹, Xiaoling Qu², Sune Kobberup¹, Jan Jensen¹, Jan Jensen² - Show less +3 more•Institutions (2)

Anschutz Medical Campus¹, Cleveland Clinic²

01 Jan 2011-Developmental Biology

TL;DR: It is concluded that FGF10 mediated mesenchymal-to-epithelial signaling maintains the progenitor niche in the embryonic duodenum primarily by repressing cell differentiation, rather than through mitogenic signaling.

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17 citations

Additional excerpts

...…as unusual as one could assume, and has been observed in for example muscle cells (Miyamoto et al., 1998), embryonic stem cells (Dvorak et al., 2005) and many cancers (Powers et al., 2000), and we therefore find it likely that autocrine signaling is also taking place in the pPdx1-Fgf10FLAG model....
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..., 2005) and many cancers (Powers et al., 2000), and we therefore find it likely that autocrine signaling is also taking place in the pPdx1-Fgf10 model....
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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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