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•

Heparin and fibroblast growth factors affect surfactant protein gene expression in type II cells.

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Kevin A. Leiner¹, Donna R. Newman, Cheng-Ming Li, Eric Walsh, Jody Khosla, Philip L. Sannes - Show less +2 more•Institutions (1)

North Carolina State University¹

22 Jun 2006-American Journal of Respiratory Cell and Molecular Biology

TL;DR: Hemparin can be stimulatory to SP gene expression depending on concentration, degree of sulfation, and surrounding FGF environment, and that heparin plays a significant role in modulating alveolar epithelial cell phenotype in vitro.

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Abstract: The stimulation and maintenance of the pulmonary alveolar type II cell's capacity to biosynthesize, store, and secrete surfactant proteins (SPs) are modulated to a great extent by growth factors, extracellular matrix (ECM) components, and hormones It is possible that differences in ECM composition, as exist between type I and II cells normally or as might occur with excessive cell surface shedding during inflammation or injury states, may specifically alter SP expression Here, isolated type II cells were exposed to the model sulfated ECM heparin; desulfated heparin; and/or fibroblast growth factor (FGF)-1, -2, or -7 for 24 h to examine by quantitative real-time polymerase chain reaction their effects on SP gene expression Aquaporin 5 (AQP-5) gene expression was also examined as a phenotypic marker for the type I cell SP-B mRNA abundance was increased 4- to 8-fold by all three FGFs Heparin at low concentrations (5 microg/ml) or desulfated heparin at high concentrations (500 microg/ml) enhanced the effects of FGF-2 and -7, while high heparin concentrations (500 microg/ml) were inhibitory In contrast, SP-B mRNA abundance was increased by heparin in a dose- and sulfation-dependent manner when used in combination with FGF-1 SP-C and AQP-5 mRNA levels were increased by heparin alone in a dose- and sulfation-dependent manner, while all FGFs lacked effect on SP-C or AQP-5 mRNA levels These data indicate that heparin can be stimulatory to SP gene expression depending on concentration, degree of sulfation, and surrounding FGF environment, and that heparin plays a significant role in modulating alveolar epithelial cell phenotype in vitro

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12 citations

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

...It is possible that this differential modulation of the actions of FGF-1, FGF-2, or FGF-7 by heparin may be due to the differences in the receptors that bind each ligand, as FGF-1 and FGF-2 can exert their actions through multiple FGF receptor (FGFR) types, while FGF-7 binds only to a single form of the receptor that is uniquely expressed in epithelial cells, FGFR-2, IIIb (KGFR) (43)....
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...However, LaRochelle and coworkers (38) demonstrated that high heparin concentrations inhibited the binding and signaling of FGF-7 at the KGFR, but did not inhibit the binding and signaling of FGF-1 (which also binds to KGFR) in Chinese hamster ovary cells that were transfected with a KGFR-encoding cDNA....
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Journal Article•DOI•

Synectin-dependent gene expression in endothelial cells

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Anthony A. Lanahan¹, Thomas Chittenden¹, Eileen R. Mulvihill², Kimberly C. Smith², Stephen M. Schwartz², Michael Simons¹ - Show less +2 more•Institutions (2)

Dartmouth–Hitchcock Medical Center¹, University of Washington²

01 Dec 2006-Physiological Genomics

TL;DR: Aberrant biological processes of transcriptional regulation in synectin(-/-) primary endothelial cells are identified including abnormal basal regulation of genes associated with development, cell organization and biogenesis, intracellular tracking, and cell adhesion.

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Abstract: Synectin (GIPC1), a receptor scaffold protein, has been isolated by our laboratory as a syndecan-4 cytoplasmic domain binding partner that regulates important aspects of cell motility (Gao Y, Li M,...

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12 citations

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

...FIBROBLAST GROWTH FACTORS have long been thought to stimulate intracellular signaling by binding to high affinity receptors (FGF receptors 1–4) that belong to the classic transmembrane tyrosine kinase family of receptors (19)....
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Journal Article•DOI•

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

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Jiaoting Zheng, Wei Zhang, Linfeng Li, Yi He, Yue Wei, Yongjun Dang, Shenyou Nie, Zufeng Guo - Show less +4 more

14 Apr 2022-Frontiers in Chemistry

TL;DR: This review starts by introducing the biological basis of FGF/FGFR signaling, then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of Small-Molecule-based therapies of different modalities.

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Abstract: Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.

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12 citations

Journal Article•DOI•

Basic fibroblast growth factor increases intracellular magnesium concentration through the specific signaling pathways.

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Bing-Zhe Hong¹, Sun-Ah Park¹, Han-Na Kim¹, Tian-Ze Ma¹, Han-Gyu Kim¹, Hyung-Sub Kang¹, Hwan-Gyu Kim¹, Yong-Geun Kwak¹ - Show less +4 more•Institutions (1)

Chonbuk National University¹

08 Jul 2009-Molecules and Cells

TL;DR: Results suggest that bFGF increases the [Mg2+]i from the intracellular Mg 2+ stores through the tyrosine kinase/PI3K/PLCγ-dependent signaling pathways.

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Abstract: Basic fibroblast growth factor (bFGF) plays an important role in angiogenesis. However, the underlying mechanisms are not clear. Mg2+ is the most abundant intracellular divalent cation in the body and plays critical roles in many cell functions. We investigated the effect of bFGF on the intracellular Mg2+ concentration ([Mg2+]i) in human umbilical vein endothelial cells (HUVECs). bFGF increased [Mg2+]i in a dose-dependent manner, independent of extracellular Mg2+. This bFGF-induced [Mg2+]i increase was blocked by tyrosine kinase inhibitors (tyrphostin A-23 and genistein), phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY294002) and a phospholipase Cγ (PLCγ) inhibitor (U73122). In contrast, mitogen-activated protein kinase inhibitors (SB202190 and PD98059) did not affect the bFGF-induced [Mg2+]i increase. These results suggest that bFGF increases the [Mg2+]i from the intracellular Mg2+ stores through the tyrosine kinase/PI3K/PLCγ-dependent signaling pathways.

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12 citations

Journal Article•DOI•

Potential Therapeutic Effects of Gut Hormones, Ghrelin and Obestatin in Oral Mucositis.

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Agnieszka Stempniewicz¹, Piotr Ceranowicz¹, Zygmunt Warzecha¹•Institutions (1)

Jagiellonian University Medical College¹

27 Mar 2019-International Journal of Molecular Sciences

TL;DR: The ghrelin and obestatin are focused on as potentially useful candidates for the prevention and treatment of chemo- or/and radiotherapy-induced oral mucositis.

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Abstract: Chemotherapy and/or head and neck radiotherapy are frequently associated with oral mucositis. Oral pain, odynophagia and dysphagia, opioid use, weight loss, dehydration, systemic infection, hospitalization and introduction of a feeding tube should be mentioned as the main determinated effect of oral mucositis. Oral mucositis leads to a decreased quality of life and an increase in treatment costs. Moreover, oral mucositis is a life-threatening disease. In addition to its own direct life-threatening consequences, it can also lead to a reduced survival due to the discontinuation or dose reduction of anti-neoplasm therapy. There are numerous strategies for the prevention or treatment of oral mucositis; however, their effectiveness is limited and does not correspond to expectations. This review is focused on the ghrelin and obestatin as potentially useful candidates for the prevention and treatment of chemo- or/and radiotherapy-induced oral mucositis.

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12 citations

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

...KGF was originally isolated from the conditioned medium of a human fibroblast cell line as a growth factor specific for epithelial cells [55]....
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...For this reason, the loss of regulation at any stage of the signal transduction cascades of FGFs may promote cell growth beyond control, leading to neoplastic growth [55]....
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...KGF belongs to the fibroblast growth factor family and is also known as fibroblast growth factor-7 [55]....
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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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