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 expression profiles of fibroblast growth factor 9 and its receptors in developing mice testes

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Meng Shao Lai¹, Chia Yih Wang¹, Shang Hsun Yang¹, Chia Ching Wu¹, H. Sunny Sun¹, Shaw Jenq Tsai¹, Jih Ing Chuang¹, Yung Chia Chen², Bu Miin Huang¹ - Show less +5 more•Institutions (2)

National Cheng Kung University¹, Kaohsiung Medical University²

14 Apr 2016-Organogenesis

TL;DR: Results show that FGF9 is correlated with the temporal expression profiles of FGFR2 and FGFR3 and possibly associated with testis development, and strongly suggest that the essential role of FGF 9 in testicular organogenesis and maturation remains elusive.

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Abstract: An expressional lack of fibroblast growth factor 9 (FGF9) would cause male-to-female sex reversal in the mouse, implying the essential role of FGF9 in testicular organogenesis and maturation. However, the temporal expression of FGF9 and its receptors during testicular development remains elusive. In this study, immunohistochemistry was used to identify the localization of FGF9 and its receptors at different embryonic and postnatal stages in mice testes. Results showed that FGF9 continuously expressed in the testis during development. FGF9 had highest expression in the interstitial region at 17-18 d post coitum (dpc) and in the spermatocytes, spermatids and Leydig cell on postnatal days (pnd) 35-65. Regarding receptor expression, FGFR1 and FGFR4 were evenly expressed in the whole testis during the embryonic and postnatal stages. However, FGFR2 and FGFR3 were widely expressed during the embryonic testis development with higher FGFR2 expression in seminiferous tubules at 16-18 dpc and higher FGFR3 expression in interstitial region at 17-18 dpc. In postnatal stage, FGFR2 extensively expressed with higher expression at spermatids and Leydig cells on 35-65 pnd and FGFR3 widely expressed in the whole testis. Taken together, these results strongly suggest that FGF9 is correlated with the temporal expression profiles of FGFR2 and FGFR3 and possibly associated with testis development.

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9 citations

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

...FGFs have at least 18 members 8-10 with biological functions by interaction with its conjugate receptor, FGFRs.(11,12) Indeed, it has been well demonstrated that FGF signaling participates in gonad organogenesis....
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...Luteinizing hormone (LH), which is released from the pituitary gland, induces the Leydig cells to produce testosterone, induce the development of secondary sex characteristics, and promote sexual maturation in puberty.7 FGFs have at least 18 members 8-10 with biological functions by interaction with its conjugate receptor, FGFRs.11,12 Indeed, it has been well demonstrated that FGF signaling participates in gonad organogenesis.8,13-17 Until now, four FGFRs were identified in the human genome participating in gonad functional regulations: FGFR1 maintains undifferentiated spermatogonia in mice; FGFR2 participates in sex determination and testis cord formation; FGFR3 is proven to be the pre-/spermatogonia maker associated with spermatogonial survival; and FGFR4 is involved in myogenesis and muscle regeneration with an expression level in the seminiferous epithelium.18-22 In addition to genomic differences, mRNA of FGFRs could undergo alternative splicing to increase the protein diversity of FGFRs....
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...Thus, different FGFs could interact with their specific FGFRs to pass different signal into cells.(11,23-25) In fact, FGFFGFR signaling has been demonstrated to participate in mitogenesis, migration, embryogenesis, differentiation, tumorigenesis, and angiogenesis....
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Journal Article•DOI•

Effects of FGFR4 G388R, V10I polymorphisms on the likelihood of cancer

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Tao Peng¹, Yangyang Sun², Zhiwei Lv², Ze Zhang², Quanxin Su², Hao Wu², Wei Zhang, Wei Yuan, Li Zuo², Li Shi², Lifeng Zhang², Xiaoli Zhou², Yuanyuan Mi¹ - Show less +9 more•Institutions (2)

Jiangnan University¹, Nanjing Medical University²

14 Jan 2021-Scientific Reports

TL;DR: The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously as discussed by the authors.

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Abstract: The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03-1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04-1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.

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9 citations

Journal Article•DOI•

Isolation, characterization, and expression analysis of FGF5 isoforms in cashmere goat

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Xiaolin He¹, Chao Yuan¹, Yinglong Chen¹•Institutions (1)

Northwest A&F University¹

01 Feb 2014-Small Ruminant Research

TL;DR: Results from the present study suggested that FGF5 gene may play a crucial role in cashmere goat hair growth cycle, and homologous comparison with various species indicated that cgFGF4 gene implied good evolutional conservation in sequence.

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9 citations

Journal Article•DOI•

Structural interactomics: informatics approaches to aid the interpretation of genetic variation and the development of novel therapeutics

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Semin Lee¹, Alan Brown¹, William R. Pitt¹, Alicia P. Higueruelo¹, Sungsam Gong¹, George Richard Bickerton¹, Adrian Schreyer¹, Duangrudee Tanramluk¹, Alison Baylay¹, Tom L. Blundell¹ - Show less +6 more•Institutions (1)

University of Cambridge¹

12 Nov 2009-Molecular BioSystems

TL;DR: The applicability of a structural interactomics approach to the study of the fibroblast growth factor-stimulated mitogen-activated protein kinase (MAPK) pathway is demonstrated.

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Abstract: Here we review the use of informatics in structural interactomics, with particular emphasis on understanding interfacial contacts in the development of novel therapeutics and the interpretation of genetic variation. We describe the availability and applicability of structural databases of protein interactions which facilitate this endeavour. We demonstrate the applicability of a structural interactomics approach to the study of the fibroblastgrowth factor (FGF)-stimulated mitogen-activated protein kinase (MAPK) pathway.

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9 citations

Journal Article•DOI•

Fgfr2b signaling is essential for the maintenance of the alveolar epithelial type 2 lineage during lung homeostasis in mice

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Negah Ahmadvand, Arun Lingampally, Farhad Khosravi, Ana Ivonne Vazquez-Armendariz, Stefano Rivetti, Matthew R Jones, Jochen Wilhelm, Susanne Herold, Guillermo Barreto, Janine Koepke, Christos Samakovlis, Gianni Carraro, Jinsan Zhang, Denise Al Alam, Saverio Bellusci - Show less +11 more

28 Jan 2022-Cellular and Molecular Life Sciences

TL;DR: In this paper , the authors used tamoxifen exposure for either 1 or 2 weeks to delete fibroblast growth factor receptor 2b (Fgfr2b) expression in cells belonging to the alveolar epithelial type 2 cells (AT2s) homeostasis.

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Abstract: Fibroblast growth factor receptor 2b (Fgfr2b) signaling is essential throughout lung development to form the alveolar epithelial lineage. However, its role in alveolar epithelial type 2 cells (AT2s) homeostasis was recently considered dispensable. SftpcCreERT2; Fgfr2bflox/flox; tdTomatoflox/flox mice were used to delete Fgfr2b expression in cells belonging to the AT2 lineage, which contains mature AT2s and a novel SftpcLow lineage-traced population called "injury activated alveolar progenitors" or IAAPs. Upon continuous tamoxifen exposure for either 1 or 2 weeks to delete Fgfr2b, a shrinking of the AT2 population is observed. Mature AT2s exit the cell cycle, undergo apoptosis and fail to form alveolospheres in vitro. However, the lung morphometry appears normal, suggesting the involvement of compensatory mechanisms. In mutant lungs, IAAPs which escaped Fgfr2b deletion expand, display enhanced alveolosphere formation in vitro and increase drastically their AT2 signature, suggesting differentiation towards mature AT2s. Interestingly, a significant increase in AT2s and decrease in IAPPs occurs after a 1-week tamoxifen exposure followed by an 8-week chase period. Although mature AT2s partially recover their alveolosphere formation capabilities, the IAAPs no longer display this property. Single-cell RNA seq analysis confirms that AT2s and IAAPs represent stable and distinct cell populations and recapitulate some of their characteristics observed in vivo. Our results underscore the essential role played by Fgfr2b signaling in the maintenance of the AT2 lineage in the adult lung during homeostasis and suggest that the IAAPs could represent a new population of AT2 progenitors.

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9 citations

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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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