A six-amino acid deletion in basic fibroblast growth factor dissociates its mitogenic activity from its plasminogen activator-inducing capacity.

Isacchi, Antonella; Statuto, Massimo; Chiesa, Roberta; Bergonzoni, Laura; Rusnati, Marco; Sarmientos, Paolo; Ragnotti, Giovanni; Presta, Marco

doi:10.1073/pnas.88.7.2628

Cited by 73 publications

(33 citation statements)

References 29 publications

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“…In agreement with this hypothesis, we demonstrated that the mitogenic activity and urokinase-type plasminogen activator (uPA)-inducing capacity of FGF-2 are mediated by different signal transduction pathways in cultured endothelial GM 7373 cells (Presta et al, 1989). However, we observed also that different FGF-2 mutants devoid of the capacity to up-regulate uPA production in endothelial cells still retain receptor-binding activity and full mitogenic capacity (Isacchi et al, 1991;Presta et al, 1992Presta et al, , 1993, raising the question of the role exerted by TK-FGFR in transducing the uPA-inducing signal. This was examined also in light of the complexity of the mechanism of interaction of FGF-2 with the endothelial cell.…”

Section: Introductionsupporting

confidence: 72%

“…However, this interaction differs from that responsible for mitogenicity, as suggested by the biological properties of different FGF-2 mutants (Isacchi et al, 1991;Presta et al, 1992Presta et al, , 1993 and confirmed by the experiments performed here with various FGF-2 antagonists.…”

Section: Fgf-2 Antagonists and Upa Up-regulationmentioning

confidence: 66%

“…No increase in cell-associated uPA activity and uPA mRNA expression was observed in mocktransfected CHO cells ( Figure 4B). As observed for GM 7373 cells, high concentrations of heparin (100 ,tg/ml) or of soluble FGFR-1 (300 ,ug/ml) did not prevent uPA up-regulation induced by FGF-2 in CHOflg7G cells, and the FGF-2 mutants M1-FGF-2 and M6B-FGF-2, which are unable to induce uPA production in endothelial cells (Isacchi et al, 1991;Presta et al, 1992), were also ineffective in this clone (our unpublished observation). FGF-2 (ng/ml) FGF dometrial adenocarcinoma HEC-1-B cells (Presta et al, 1988).…”

Section: Fgf-2 Antagonists and Upa Up-regulationmentioning

confidence: 91%

“…Human recombinant FGF-2 was expressed and purified from transformed Escherichia coli cells by heparin-Sepharose chromatography as described (Isacchi et al, 1991). Synthetic peptides representing amino acid residues FGF-2(112-155) and , where amino acid numbering 1-155 is utilized for FGF-2, were a gift of A. Baird (The Whittier Institute, La Jolla, CA).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…Human recombinant FGF-2 was labeled with Na125I (37 GBq/ml; Amersham International, Amersham, UK) using lodogen (Pierce Chemical, Rockford, IL) as described (Isacchi et al, 1991). Twentyfour hours after plating in 24-well dishes at the density of 70,000 cells/cm2, cells were washed three times with ice-cold PBS and incubated for 2 h at 4°C in binding medium (serum-free medium containing 0.15% gelatin, 20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.5) with 10 ng/ml of liposome-associated or free 1251I-FGF-2.…”

Section: I-fgf-2 Binding and Internalization Assaysmentioning

confidence: 99%

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A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

Rusnati

Dell’Era

Urbinati

et al. 1996

MBoC

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Basic fibroblast growth factor (FGF-2) induces cell proliferation and urokinase-type plasminogen activator (uPA) production in fetal bovine aortic endothelial GM 7373 cells. In the present paper we investigated the role of the interaction of FGF-2 with tyrosinekinase (TK) FGF receptors (FGFRs) in mediating uPA up-regulation in these cells. The results show that FGF-2 antagonists suramin, protamine, heparin, the synthetic peptide FGF-2(112-155), and a soluble form of FGFR-1 do not inhibit FGF-2-mediated uPA up-regulation at concentrations that affect growth factor binding to cell surface receptors and mitogenic activity. In contrast, tyrosine phosphorylation inhibitors and overexpression of a dominant negative TK-mutant of FGFR-1 abolish the uPA-inducing activity of FGF-2, indicating that FGFR and its TK activity are essential in mediating uPA induction. Accordingly, FGF-2 induces uPA up-regulation in Chinese hamster ovary cells transfected with wild-type FGFR-1, -2, -3, or -4 but not with TK-FGFR-1 mutant. Small unilamellar phosphatidyl choline:cholesterol vesicles loaded with FGF-2 increased uPA production in GM 7373 cells in the absence of a mitogenic response. Liposome-encapsulated FGF-2 showed a limited but significant capacity, relative to free FGF-2, to interact with FGFR both at 4°C and 37°C and to be internalized within the cell. uPA up-regulation by liposome-encapsulated FGF-2 was quenched by neutralizing anti-FGF-2 antibodies, indicating that the activity of liposome-delivered FGF-2 is mediated by an extracellular action of the growth factor. Taken together, the data indicate that a distinct interaction of FGF-2 with FGFR, quantitatively and/or qualitatively different from the one that leads to mitogenicity, is responsible for the uPA-inducing activity of the growth factor.

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Section: Introductionsupporting

confidence: 72%

Section: Fgf-2 Antagonists and Upa Up-regulationmentioning

confidence: 66%

Section: Fgf-2 Antagonists and Upa Up-regulationmentioning

confidence: 91%

Section: Materials and Methods Materialsmentioning

confidence: 99%

Section: I-fgf-2 Binding and Internalization Assaysmentioning

confidence: 99%

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A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

Rusnati

Dell’Era

Urbinati

et al. 1996

MBoC

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Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury

et al. 1996

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Given the evidence that basic fibroblast growth factor (FGF-2) can protect neural and retinal cells from degeneration, we evaluated the potential of this growth factor to protect sensory cells in the inner ear. When sensory cells of the organ of Corti are exposed to aminoglycoside antibiotics such as neomycin either in vivo or in vitro, significant ototoxicity is observed. The in vitro cytotoxic effects of neomycin are dose and time dependent. In neonatal rat organ of Corti cultures, complete inner and outer hair cell destruction is observed at high (mM) concentrations of neomycin while inner hair cell survival and severely damaged outer hair cells are noted at moderate (microM) concentrations, with a maximal effect observed after 2 days of culture. Approximately 50% of cochlear outer hair cells are lost at a dose of 35 microM neomycin, and most surviving cells show disorganized stereocilia. Inner hair cells show primarily disorganization of their stereocilia. A significant protective effect is observed when the organ of Corti is pre-treated with FGF-2 (500 ng/ml) for 48 hours, and then FGF-2 is included with neomycin in the culture medium. A greater extent of outer hair cell survival and a significant decrease in stereociliary damage are noted with FGF-2. However, disorganization of inner hair cell stereocilia is unaffected by FGF-2. The protective effect of FGF-2 is specific, since interleukin-1B, nerve growth factor, tumor necrosis factor, and epidermal growth factor are ineffective, while retinoic acid and transforming growth factor alpha show only a moderate protective effect. These results confirm the potential of molecules like FGF-2 for preventing cell death due to a variety of causes.

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SPARC antagonizes the effect of basic fibroblast growth factor on the igration of bovine aortic endothelial cells

Hasselaar

Sage

1992

J of Cellular Biochemistry

134

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Migration of endothelial cells is requisite to wound repair and angiogenesis. Since the glycoprotein SPARC (secreted protein, acidic and rich in cysteine) is associated with remodeling, cellular migration, and angiogenesis in vitro, we questioned whether SPARC might influence the motility of endothelial cells. In this study we show that, in the absence of serum, exogenous SPARC inhibits the migration of bovine aortic endothelial cells induced by bFGF. Similar results were obtained from two different assays, in which cell migration was measured in a Boyden chamber and in monolayer culture after an experimental wound. Without bFGF, the migration of endothelial cells was unaffected by SPARC. The inhibitory effect of SPARC on cell motility was dose-dependent, required the presence of Ca2+, was mimicked by synthetic peptides from the N- and C-terminal Ca(2+)-binding domains of the protein, and was not seen in the presence of serum. Modulation of the activities of secreted and cell-associated proteases, including plasminogen activators and metalloproteinases, appeared not to be responsible for the effects that we observed on the motility of endothelial cells. Moreover, a molecular interaction between SPARC and bFGF was not detected, and SPARC did not interfere with the binding of bFGF to high-affinity receptors on endothelial cells. Finally, in culture medium that contained serum, SPARC inhibited the incorporation of [3H]-thymidine into newly synthesized DNA, both in the absence and presence of bFGF. However, DNA synthesis was not affected by SPARC when the cells were plated on gelatin or fibronectin in serum-free medium. We propose that the combined action of a serum factor and SPARC regulates both endothelial cell proliferation and migration and coordinates these events during morphogenetic processes such as wound repair and angiogenesis.

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A six-amino acid deletion in basic fibroblast growth factor dissociates its mitogenic activity from its plasminogen activator-inducing capacity.

Cited by 73 publications

References 29 publications

A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

A distinct basic fibroblast growth factor (FGF-2)/FGF receptor interaction distinguishes urokinase-type plasminogen activator induction from mitogenicity in endothelial cells.

Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury

SPARC antagonizes the effect of basic fibroblast growth factor on the igration of bovine aortic endothelial cells

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