A Novel Alternatively Spliced Fibroblast Growth Factor Receptor 3 Isoform Lacking the Acid Box Domain Is Expressed during Chondrogenic Differentiation of ATDC5 Cells

Shimizu, Akio; Tada, Kouichirou; Shukunami, Chisa; Hiraki, Yuji; Kurokawa, Tsutomu; Magane, Noriko; Kurokawa-Seo, Misuzu

doi:10.1074/jbc.m003535200

Cited by 51 publications

(44 citation statements)

References 56 publications

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“…Although the major ligand-binding determinant for FGF receptors comprises the IG2 and IG3 domains, the alternative EGL-15-specific inserts are situated in a region that could easily affect ligand-binding affinity. In fact, other regions of the extracellular domain are known to modify ligand-binding affinity (Shimizu et al, 2001;Wang et al, 1995). Considering the decreased efficiency of heterologous ligand rescue, it remains possible that differences in ligand-receptor affinities contribute to the mechanism by which the different ligands stimulate different biological events.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing affecting a novel domain in theC. elegansEGL-15 FGF receptor confers functional specificity

et al. 2003

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Fibroblast growth factor (FGF) receptors trigger a wide variety of cellular responses as diverse as cell migration, cell proliferation and cell differentiation. However, the molecular basis of the specificity of these responses is not well understood. The C. elegans FGF receptor EGL-15 similarly mediates a number of different responses, including transducing a chemoattractive signal and mediating an essential function. Analysis of the migration-specific alleles of egl-15 has identified a novel EGL-15 isoform that provides a molecular explanation for the different phenotypic effects of lesions at this locus. Alternative splicing yields two EGL-15 proteins containing different forms of a domain located within the extracellular region of the receptors immediately after the first IG domain. Neither of these two domain forms is found in any other FGF receptor. We have tested the roles of these EGL-15 receptor isoforms and their two FGF ligands for their signaling specificity. Our analyses demonstrate different physiological functions for the two receptor variants. EGL-15(5A) is required for the response to the FGF chemoattractant that guides the migrating sex myoblasts to their final positions. By contrast, EGL-15(5B) is both necessary and sufficient to elicit the essential function mediated by this receptor.

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Section: Discussionmentioning

confidence: 99%

Alternative splicing affecting a novel domain in theC. elegansEGL-15 FGF receptor confers functional specificity

et al. 2003

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“…Detection of Apoptosis by Flow Cytometry RT112 cells were plated overnight into 35-mm tissue culture dishes and treated with 0.2 Amol/L 3C, immunotoxins, or rGel in complete RPMI 1640 at various times (24,48, and 72 h). After that, both adherent and floating cells were collected and apoptosis was measured with FITC-conjugated Annexin V antibody and propidium iodide (PI) using Annexin V-FITC Apoptosis Detection kit I (BD PharMingen) according to the instructions from the manufacturer.…”

Section: Antibody-mediated Internalization Assaymentioning

confidence: 99%

“…In contrast, expression of the IIIc variant was generally associated with mesenchymal-derived cell lineages and binds a wide range of FGFs. Other isoforms have been described, some of which result in frame shifts and early termination in exon 10 region, where others showed deleted domains but still in-frame (24,25). Characterization of these variants has led to the hypothesis that aberrant splicing of FGFR3 mRNA may result in a selective advantage for cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis

Martı́nez-Torrecuadrada

Cheung

López-Serra

et al. 2008

Molecular Cancer Therapeutics

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Human single-chain Fv directed against fibroblast growth factor receptor 3 (FGFR3) have been shown to block proliferation of RT112 bladder carcinoma cells in vitro. Here, we examined the ability of the recombinant gelonin toxin (rGel) to enhance this inhibitory effect in vitro and in vivo on the bladder cancer cell line RT112 and the corresponding xenografts. Immunotoxins were genetically engineered by fusing FGFR3-specific Fv fragments (3C) to the NH 2 terminus of rGel and expressed as a soluble protein in Escherichia coli. The 3C/rGel fusion construct showed an IC 50 of 200 nmol/L against log-phase RT112 cells compared with 1,500 nmol/L for free rGel. Immunofluorescence studies showed that the 3C/rGel construct internalized rapidly into the cytoplasm of RT112 cells within 1 h of exposure. The mechanism of immunotoxininduced cell death was found to be mediated by apoptosis. RT112 tumor xenografts in severe combined immunodeficient mice treated with 50 mg/kg 3C/rGel exhibited considerable growth delay relative to control tumors and a significant reduction of 55% to 70% in mean tumor size. Immunohistochemical analysis showed that tumors from mice treated with 3C/rGel displayed considerable apoptotic damage compared with control groups. Subcellular location of FGFR3 in immunotoxin-treated tumors indicated a translocation of FGFR3 to the nuclear membrane in contrast to tumors from saline-treated controls. These results show that FGFR3-driven immunotoxins may be an effective therapeutic agent against human bladder and other tumor types overexpressing FGFR3. [Mol Cancer Ther 2008;7(4):862 -73]

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“…FGF receptors are characterized by their cytoplasmic tyrosine kinase enzymatic activity. These receptors exist in several isoforms and display a range of affinities for individual FGFs, resulting in the induction of specific cellular responses (13,14). FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, and FGFR4 have been detected in total cellular extracts of the embryonic pancreas by semiquantitative RT-PCR (11).…”

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confidence: 99%

FGFR3 Is a Negative Regulator of the Expansion of Pancreatic Epithelial Cells

et al. 2007

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1Fibroblast growth factors (FGFs) and their receptors (FGFRs) are key signaling molecules for pancreas development. Although FGFR3 is a crucial developmental gene, acting as a negative regulator of bone formation, its participation remains unexplored in pancreatic organogenesis. We found that FGFR3 was expressed in the epithelia in both mouse embryonic and adult regenerating pancreata but was absent in normal adult islets. In FGFR3 knockout mice, we observed an increase in the proliferation of epithelial cells in neonates, leading to a marked increase in islet areas in adults. In vitro studies showed that FGF9 is a very potent ligand for FGFR3 and activates extracellular signal-related kinases (ERKs) in pancreatic cell lines. T he pancreas is derived from evaginations of the foregut endoderm during midgestation. At this time, ventral and dorsal pancreatic buds grow, branch, and fuse to form the functionally primitive pancreas (rev. in 1). Pancreatic gene expression studies have identified a number of factors involved in the differentiation and maintenance of islet progenitor cells (rev. in 2,3). Moreover, pancreatic development depends on mesenchymal/epithelial interactions (4). Among the growth factors involved in pancreatic organogenesis, fibroblast growth factors (FGFs) are candidates considered to mediate the process of branching morphogenesis (5). FGF expression has been demonstrated in the developing pancreas (6 -8), and altered expression of specific FGFs can affect pancreatic differentiation (9 -12).FGFs, which constitute a family of at least 23 members, bind and activate the FGF receptors (FGFRs), encoded by four genes in the mouse (named FGFR1-4). FGF receptors are characterized by their cytoplasmic tyrosine kinase enzymatic activity. These receptors exist in several isoforms and display a range of affinities for individual FGFs, resulting in the induction of specific cellular responses (13,14). FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, and FGFR4 have been detected in total cellular extracts of the embryonic pancreas by semiquantitative RT-PCR (11). The FGFR1-IIIb isoform is a putative pancreatic progenitor cell marker, based on in vitro studies and on the distribution of its transcripts during pancreatic development (15). In addition, adult mice with attenuated FGFR1c signaling display impaired ␤-cell function (16). In vitro and in vivo studies have shown that the FGFR2-IIIb isoform is required for endocrine precursor cell proliferation (17,18). Interestingly, FGFR1 and FGFR4 are expressed early in pancreatic development (before embryonic day [E]16), but their expression diminishes by adulthood (7). FGFR3 is detected in the adult human pancreas (19) and in the developing mouse pancreas (11), but very little is known regarding its role during pancreatic growth.FGFR3 is a developmental gene, and its critical role in bone development has been elegantly described. Lack of FGFR3 leads to skeletal overgrowth and deafness (20), while gain of function mutations, rendering the receptor constitutively active, cau...

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A Novel Alternatively Spliced Fibroblast Growth Factor Receptor 3 Isoform Lacking the Acid Box Domain Is Expressed during Chondrogenic Differentiation of ATDC5 Cells

Cited by 51 publications

References 56 publications

Alternative splicing affecting a novel domain in theC. elegansEGL-15 FGF receptor confers functional specificity

Alternative splicing affecting a novel domain in theC. elegansEGL-15 FGF receptor confers functional specificity

Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis

FGFR3 Is a Negative Regulator of the Expansion of Pancreatic Epithelial Cells

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