scholarly journals Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 899 ◽  
Author(s):  
Anna Szlachcic ◽  
Martyna Sochacka ◽  
Aleksandra Czyrek ◽  
Lukasz Opalinski ◽  
Daniel Krowarsch ◽  
...  
Keyword(s):  
Thermodynamic Stability ◽  
Proliferative Response ◽  
Specific Binding ◽  
Integrin Αvβ3 ◽  
Proteolytic Degradation ◽  
Fibroblast Growth ◽  
Mitogenic Response ◽  
Downstream Signaling ◽  
Mitogenic Potential ◽  
Proliferation Potential

Fibroblast growth factor 1 (FGF1) has been shown to interact with integrin αvβ3 through a specific binding site, involving Arg35 residue. The FGF1 mutant (R35E) with impaired integrin binding was found to be defective in its proliferative response, although it was still able to interact with FGF receptors (FGFR) and heparin and induce the activation of downstream signaling pathways. Here, we demonstrate that the lack of mitogenic potential of R35E mutant is directly caused by its decreased thermodynamic stability and susceptibility to proteolytic degradation. Introduction of three stabilizing mutations into R35E variant compensated the effect of destabilizing R35E mutation and restored the proliferation potential of FGF1. Moreover, the stabilized R35E variant regained both anti-apoptotic and wound healing activities, while remaining defective in binding to integrin αvβ3. Our results suggest that the thermodynamic stability and resistance to degradation, rather than the interaction with integrin are required for mitogenic response of FGF1.

Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression

2018 ◽  
Vol 19 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Liwei Lang ◽  
Austin Y. Shull ◽  
Yong Teng
Keyword(s):  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Tumor Development ◽  
Vital Role ◽  
Signaling Cascades ◽  
Cancer Cell Proliferation ◽  
Clinical Use ◽  
Fibroblast Growth ◽  
Apoptosis Resistance ◽  
Downstream Signaling

Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.

scholarly journals Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation.

1988 ◽  
Vol 107 (2) ◽  
pp. 743-751 ◽  
Author(s):  
O Saksela ◽  
D Moscatelli ◽  
A Sommer ◽  
D B Rifkin
Keyword(s):  
Growth Factor ◽  
Heparan Sulfate ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Deae Cellulose ◽  
Proteolytic Degradation ◽  
Fibroblast Growth ◽  
Intact Cells ◽  
High Affinity ◽  
Cell Extracts

Cultured bovine capillary endothelial (BCE) cells were found to synthesize and secrete high molecular mass heparan sulfate proteoglycans and glycosaminoglycans, which bound basic fibroblast growth factor (bFGF). The secreted heparan sulfate molecules were purified by DEAE cellulose chromatography, followed by Sepharose 4B chromatography and affinity chromatography on immobilized bFGF. Most of the heparinase-sensitive sulfated molecules secreted into the medium by BCE cells bound to immobilized bFGF at low salt concentrations. However, elution from bFGF with increasing salt concentrations demonstrated varying affinities for bFGF among the secreted heparan sulfate molecules, with part of the heparan sulfate requiring NaCl concentrations between 1.0 and 1.5 M for elution. Cell extracts prepared from BCE cells also contained a bFGF-binding heparan sulfate proteoglycan, which could be released from the intact cells by a short proteinase treatment. The purified bFGF-binding heparan sulfate competed with 125I-bFGF for binding to low-affinity binding sites but not to high-affinity sites on the cells. Heparan sulfate did not interfere with bFGF stimulation of plasminogen activator activity in BCE cells in agreement with its lack of effect on binding of 125I-bFGF to high-affinity sites. Soluble bFGF was readily degraded by plasmin, whereas bFGF bound to heparan sulfate was protected from proteolytic degradation. Treatment of the heparan sulfate with heparinase before addition of plasmin abolished the protection and resulted in degradation of bFGF by the added proteinase. The results suggest that heparan sulfate released either directly by cells or through proteolytic degradation of their extracellular milieu may act as carrier for bFGF and facilitate the diffusion of locally produced growth factor by competing with its binding to surrounding matrix structures. Simultaneously, the secreted heparan sulfate glycosaminoglycans protect the growth factor from proteolytic degradation by extracellular proteinases, which are abundant at sites of neovascularization or cell invasion.

scholarly journals Identification of a fibroblast growth factor-binding protein in Drosophila melanogaster.

1991 ◽  
Vol 11 (4) ◽  
pp. 2319-2323 ◽  
Author(s):  
J S Doctor ◽  
F M Hoffmann ◽  
B B Olwin
Keyword(s):  
Molecular Weight ◽  
Drosophila Melanogaster ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Binding Proteins ◽  
Specific Binding ◽  
Fibroblast Growth ◽  
Heparin Binding ◽  
Acidic Fibroblast Growth Factor ◽  
Heparin Binding Growth Factors

As assessed by competitive binding and protein-crosslinking experiments, Drosophila melanogaster cells possess basic fibroblast growth factor (bFGF)-specific binding proteins that are similar to FGF receptors on vertebrate cells in molecular weight and binding affinity; these D. melanogaster cells, however, have no detectable binding proteins for acidic fibroblast growth factor (aFGF). Consistent with the presence of bFGF-specific binding proteins, D. melanogaster cells degrade bFGF but not aFGF. These results indicate the conservation of heparin-binding growth factors and receptors between vertebrates and D. melanogaster.

scholarly journals Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells.

1991 ◽  
Vol 2 (9) ◽  
pp. 719-726 ◽  
Author(s):  
M Presta ◽  
L Tiberio ◽  
M Rusnati ◽  
P Dell'Era ◽  
G Ragnotti
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Mitogenic Response ◽  
Kinase C ◽  
Fetal Bovine ◽  
Induce Cell Proliferation

Basic fibroblast growth factor (bFGF) induces a protein kinase C (PKC)-dependent mitogenic response in transformed fetal bovine aortic endothelial GM 7373 cells. A long-lasting interaction of bFGF with the cell is required to induce cell proliferation. bFGF-treated cells are in fact committed to proliferate only after they have entered the phase S of the cell cycle, 12-14 h after the beginning of bFGF treatment. Before that time, the mitogenic response to bFGF is abolished by 1) removal of extracellular bFGF by suramin, 2) addition of neutralizing anti-bFGF antibodies to the culture medium, 3) inhibition of PKC activity by the protein kinase inhibitor H-7, and 4) down-regulation of PKC by cotreatment with phorbol ester. Thus the requirement for a prolonged interaction of bFGF with the cell reflects the requirement for a prolonged activation of PKC. Similar conclusions can be drawn for the PKC activators 12-O-tetradecanoyl phorbol 13-acetate and 1,2-dioctanoyl-sn-glycerol. The two molecules require 16 and 6 h, respectively, of activation of PKC to induce 50% of maximal cell proliferation. The requirement for a long-lasting activation of PKC appears to be a mechanism for the control of cell proliferation capable of discriminating among transient nonmitogenic stimuli and long-lasting mitogenic stimuli.

scholarly journals The emerging role of the fibroblast growth factor-23–klotho axis in renal regulation of phosphate homeostasis

2007 ◽  
Vol 194 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Mohammed S Razzaque ◽  
Beate Lanske
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Ion Homeostasis ◽  
Experimental Studies ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Phosphate Homeostasis ◽  
Downstream Signaling

Normal mineral ion homeostasis is tightly controlled by numerous endocrine factors that coordinately exert effects on intestine, kidney, and bone to maintain physiological balance. The importance of the fibroblast growth factor (FGF)-23–klotho axis in regulating mineral ion homeostasis has been proposed from recent research observations. Experimental studies suggest that 1) FGF23 is an important in vivo regulator of phosphate homeostasis, 2) FGF23 acts as a counter regulatory hormone to modulate the renal 1α-hydroxylase and sodium–phosphate cotransporter activities, 3) there is a trend of interrelationship between FGF23 and parathyroid hormone activities, 4) most of the FGF23 functions are conducted through the activation of FGF receptors, and 5) such receptor activation needs klotho, as a cofactor to generate downstream signaling events. These observations clearly suggest the emerging roles of the FGF23–klotho axis in maintaining mineral ion homeostasis. In this brief article, we will summarize how the FGF23–klotho axis might coordinately regulate normal mineral ion homeostasis, and how their abnormal regulation could severely disrupt such homeostasis to induce disease pathology.

Identification of a fibroblast growth factor-binding protein in Drosophila melanogaster

1991 ◽  
Vol 11 (4) ◽  
pp. 2319-2323
Author(s):  
J S Doctor ◽  
F M Hoffmann ◽  
B B Olwin
Keyword(s):  
Molecular Weight ◽  
Drosophila Melanogaster ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Binding Proteins ◽  
Specific Binding ◽  
Fibroblast Growth ◽  
Heparin Binding ◽  
Acidic Fibroblast Growth Factor ◽  
Heparin Binding Growth Factors

As assessed by competitive binding and protein-crosslinking experiments, Drosophila melanogaster cells possess basic fibroblast growth factor (bFGF)-specific binding proteins that are similar to FGF receptors on vertebrate cells in molecular weight and binding affinity; these D. melanogaster cells, however, have no detectable binding proteins for acidic fibroblast growth factor (aFGF). Consistent with the presence of bFGF-specific binding proteins, D. melanogaster cells degrade bFGF but not aFGF. These results indicate the conservation of heparin-binding growth factors and receptors between vertebrates and D. melanogaster.

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