Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2

Scotet, Emmanuel; Houssaint, Elisabeth

doi:10.1038/sj.onc.1201908

Cited by 26 publications

(19 citation statements)

References 30 publications

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“…Expression of FGFR3 IIIb appears to be associated with epithelial cells [20,32]. A switch from IIIb to IIIc can be induced by FGF1, possibly correlating with a loss of epithelial phenotype [33]. In contrast, cytokines or growth factors such EGF, TGFh and IL2, have been shown to upregulate FGFR3 IIIb expression in the intestinal epithelial cell line Caco2 [34].…”

Section: Expression Of Fgfr3 In Tissues and Its Biological Rolesmentioning

confidence: 98%

Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

L’Hôte

Knowles

2005

Experimental Cell Research

192

153

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Section: Expression Of Fgfr3 In Tissues and Its Biological Rolesmentioning

confidence: 98%

Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

L’Hôte

Knowles

2005

Experimental Cell Research

192

153

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“…In human keratinocyte SVK14 cells, the splicing switch of FGFR-2 was induced by FGF-2. 37 A similar mechanism of alternative splicing of the human NPM gene should occur upon expression of the nuclear 24 kDa FGF-2 in HeLa cells. This control could be mediated by the induction of particular splicing factors.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of a COOH‐truncated nucleophosmin resulting from alternative splicing is associated with cellular resistance to ionizing radiation in HeLa cells

Drouet

Ader

Delmas

et al. 2002

Intl Journal of Cancer

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We previously demonstrated that transfecting HeLa cells with the 24 kDa basic fibroblast growth factor-2 (FGF-2) isoform dramatically increased cell survival after irradiation. To investigate genes implicated in this radioresistance acquisition, we compared mRNA expression between radioresistant 24 kDa FGF-2-expressing cells (HeLa 3A) and radiosensitive control HeLa PINA cells using the differential display technique. Of the 32 differentially expressed mRNAs, 1 presented a significant homology with a known gene. This 378 bp fragment presented 100% identity with exon 11 and 12 of human nucleophosmin (NPM) but differed by including a part of intron 9 in its 5ℙ end. The differential expression of this fragment was confirmed using an RNase protection assay. We then cloned the entire corresponding mRNA and showed that it contained all the exons of NPM plus intron 9, suggesting that it was a splicing product of the NPM gene. This variant encoded for a 35-amino acid truncated NPM (NPM2). NPM2 expression was increased in HeLa 3A. To investigate NPM2's role in radioresistance acquisition, we transfected HeLa cells with NPM2 cDNA and analyzed survival after irradiation of the clones obtained. After transfection with NPM2, radiosensitive HeLa cells exhibited a dramatic increase in cell survival after irradiation. Taken together, our results demonstrate that expression of a COOH-truncated NPM form resulting from the alternative splicing of NPM mRNA is able to increase cell survival after irradiation and suggests that it might be involved in cellular response to ionizing radiation.

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“…For example, FGFR2c was reported to bind FGF1 and FGF2 with equal affinity, whereas FGFR2b bound FGF2 with a thousand-fold lower affinity than FGF1 (11). It has also been suggested that the expression of b and c FGFR isoforms can be "reversibly switched" by the influence of FGF1 or FGF2 (12). Aberrant receptor switching has been reported to be involved in the progression of certain tumors (13).…”

mentioning

confidence: 99%

Evidence That Heparin Saccharides Promote FGF2 Mitogenesis through Two Distinct Mechanisms

Goodger

Robinson

Murphy

et al. 2008

Journal of Biological Chemistry

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Heparin-like saccharides play an essential role in binding to both fibroblast growth factors (FGF) and their receptors at the cell surface. In this study we prepared a series of heparin oligosaccharides according to their size and sulfation level. We then investigated their affinity for FGF2 and their ability to support FGF2 mitogenesis of heparan sulfate-deficient cells expressing FGFR1c. Tetra-and hexasaccharides bound FGF2, but failed to dimerize the growth factor. Nevertheless, these saccharides promoted FGF2-mediated cell growth. Furthermore, whereas enzymatic removal of the non-reducing end 2-O-sulfate group had little effect on the 1:1 interaction with FGF2, it eliminated the mitogenic activity of these saccharides. This evidence supports the symmetric two-end model of ternary complex formation. In contrast, even at very low concentrations, octasaccharide and larger heparin fragments conferred a potent mitogenic activity that was independent of terminal 2-O-sulfation. This correlated with the ability to dimerize FGF2 in an apparently cooperative manner. This data suggests that potent mitogenic signaling results from heparin-mediated trans-dimerization of FGF2, consistent with the asymmetric model of ternary complex formation. We propose that, depending on saccharide structure, there are different architectures and modes of ternary complex assembly that differ in stability and/or efficiency of transmembrane signaling.FGF1 and FGF2 are the prototypic members of the fibroblast growth factor (FGF) 3 family. They can induce proliferation, differentiation, motility, adhesion, survival, and apoptosis of cells at both embryonic and adult stages (1, 2). A wide variety of cells express FGF1 and FGF2, for example, vascular smooth muscle cells, neurons, epithelial cells, and fibroblasts (3). FGF2 can also be released by macrophages in response to inflammation (4) or by platelets in response to vessel injury (5). FGF1 and FGF2 are potent angiogenic factors (6). Angiogenesis, the formation of new blood vessels, is important in human disease; it is induced by malignant tumors, and is a cause of arthritis and visual impairment in diabetic retinopathies. Tumors secrete pro-angiogenic molecules, such as the FGFs, in an autocrine or paracrine manner, and increased FGF levels are associated with poor prognosis for many cancers (2, 7).Heparan sulfate (HS) proteoglycans are membrane-associated co-receptors that coordinate the interaction of FGFs with their high-affinity tyrosine kinase receptors, the FGFRs (8). These high-affinity receptors are the products of distinct mammalian genes: FGFR1 (flg), FGFR2 (bek), FGFR3, and FGFR4. FGFR1-3 can be alternatively spliced to produce a, b, and c isoforms. The a isoform is secreted and may function as a soluble receptor antagonist (9). The b and c receptor variants are particularly important as they display different ligand binding specificities and affinities (10). For example, FGFR2c was reported to bind FGF1 and FGF2 with equal affinity, whereas FGFR2b bound FGF2 with a thousand-fol...

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Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2

Cited by 26 publications

References 30 publications

Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

Increased expression of a COOH‐truncated nucleophosmin resulting from alternative splicing is associated with cellular resistance to ionizing radiation in HeLa cells

Evidence That Heparin Saccharides Promote FGF2 Mitogenesis through Two Distinct Mechanisms

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