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 2 promotes microvessel formation from mouse embryonic aorta.

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Tetsu Akimoto¹, Marc R. Hammerman¹•Institutions (1)

Washington University in St. Louis¹

01 Feb 2003-American Journal of Physiology-cell Physiology

TL;DR: It is suggested that low oxygen upregulates FGFR1 expression in embryonic aorta in vitro and renders it more responsive to FGF2.

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Abstract: To delineate the roles that oxygen and fibroblast growth factors (FGFs) play in the process of angiogenesis from the embryonic aorta, we cultured mouse embryonic aorta explants (thoracic level to lateral vessels supplying the mesonephros and metanephros) in a three-dimensional type I collagen gel matrix. During 8 days of culture under 5% O2, but not room air, the addition of FGF2 to explants stimulated the formation of Gs-IB4-positive, CD31-positive, and Flk-1-positive microvessels in a concentration-dependent manner. FGF2-stimulated microvessel formation was inhibited by sequestration of FGF2 via addition of soluble FGF receptor (FGFR) chimera protein or anti-FGF2 antibodies. FGFR1 and FGFR2 were present on explants. Levels of FGFR1, but not FGFR2, were increased in embryonic aorta cultured under 5% O2 relative to room air. Our data suggest that low oxygen upregulates FGFR1 expression in embryonic aorta in vitro and renders it more responsive to FGF2.

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36 citations

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

...Among the four FGF receptors (FGFRs), FGFR1 and FGFR2 bind FGF2 with the highest affinities (15)....
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...Actions of FGF2 (9, 14, 15) are mediated via signaling through cell surface receptors, which constitute a family of four structurally related transmembrane type tyrosine kinases (15)....
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Patent•

Novel fusion molecules and uses thereof

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Doron Lipson¹, Roman Yelensky, Joel R. Greenbowe, Jie He•Institutions (1)

Foundation Medicine¹

05 Nov 2013

36 citations

Journal Article•DOI•

Breast cancer cell-derived fibroblast growth factor 2 and vascular endothelial growth factor are chemoattractants for bone marrow stromal stem cells.

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Edmond F. Ritter¹, Adam D. Perry¹, Jack C Yu, Thomas N. Wang¹, Lawton Tang, Erhard Bieberich - Show less +2 more•Institutions (1)

Georgia Regents University¹

01 Feb 2008-Annals of Surgery

TL;DR: It is demonstrated that VEGF and FGF2 induce migration of MSCs are secreted by breast cancer cells, their receptors are present on M SCs, and depletion of these growth factors reduces migration, and are therefore 2 relevant growth factors for MSC migration toward breast cancer Cells.

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Abstract: Objective:Recent efforts by the scientific community to characterize the complex interplay between different cell types involved in the development of tumors have led us to investigate the roles of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) in the development of

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36 citations

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

...To show that MSCs have receptors for FGF2 (FGFR1 and FGFR4) and VEGF (FLK1), we amplified mRNA from MSCs, and used this preparation to conduct immunoblots, and then subjected these blots to RT-PCR analysis for the presences of VEGF and FGF2 receptors.(7,8) We found that MSCs express mRNA for FGFR1, FGFR4, and VEGF (FLK1) receptors (Fig....
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Book Chapter•DOI•

Molecular basis of inner ear induction.

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Stephen T. Brown¹, Kareen Martin¹, Andrew K. Groves¹•Institutions (1)

House Ear Institute¹

01 Jan 2003-Current Topics in Developmental Biology

TL;DR: This chapter provides a critical review of recent studies relating to the molecular induction of the inner ear, and a major theme to emerge is the dependence of inner ear induction on fibroblast growth factor (FGF) signaling.

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Abstract: The induction of the vertebrate inner ear is a complex developmental process that has been under investigation for decades. The traditional tools of embryology used in most of these studies have provided a wealth of information on the subject; however, they are generally limited in focus to morphological features. Recent advances in molecular biology have provided the opportunity to study inner ear induction in ways not possible in previous years. The capacity for visualizing and manipulating gene expression in combination with more traditional embryological techniques has changed the focus of inner ear induction from morphology to changes in gene expression. This chapter provides a critical review of recent studies relating to the molecular induction of the inner ear. A major theme to emerge from these studies is the dependence of inner ear induction on fibroblast growth factor (FGF) signaling. The source(s) of these FGF signals is still not entirely clear, though the available data are consistent with a mesodermal and⧸or hindbrain origin as has been long proposed. Numerous early otic marker genes have been identified as well, and their conservation in ear induction is quite clear. Functional data regarding these genes are still largely incomplete, although a role for several of these genes in zebrafish inner ear induction has been demonstrated. As a whole, these studies have made exciting and provocative contributions to the field, thus creating a more complete and precise picture of inner ear induction.

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36 citations

Journal Article•DOI•

Targeting Tyrosine kinases in Renal Cell Carcinoma: "New Bullets against Old Guys".

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Teresa Alonso-Gordoa, María Laura García-Bermejo, Enrique Grande¹, Pilar Garrido, Alfredo Carrato, Javier Molina-Cerrillo - Show less +2 more•Institutions (1)

University of Texas MD Anderson Cancer Center¹

17 Apr 2019-International Journal of Molecular Sciences

TL;DR: An overview of the central role of these tyrosine kinases’ activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development is presented.

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Abstract: Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (VHL) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression. This change in cell biology represents a new paradigm in the treatment of metastatic renal cancer by targeting angiogenesis. Currently, there are multiple therapeutic drugs available for advanced disease, including therapies against VEGFR with successful results in patients´ survival. Other tyrosine kinases’ pathways, including PDGFR, Axl or MET have emerged as key signaling pathways involved in RCC biology. Indeed, promising new drugs targeting those tyrosine kinases have exhibited outstanding efficacy. In this review we aim to present an overview of the central role of these tyrosine kinases’ activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development. In the immunotherapy era, angiogenesis is still an “old guy” that the medical community is trying to fight using “new bullets”.

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36 citations

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

...FGFR exhibits a structure including three immunoglobulin-like extracellular domains that bind to FGFs, a transmembrane domain and an intracellular tyrosine kinase domain [87]....
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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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