Cloning, expression and tissue distribution of the gene encoding rat fibroblast growth factor receptor subtype 4

Horlick, Robert A.; Stack, Sylvia; Cooke, Gary M.

doi:10.1016/0378-1119(92)90108-2

Cited by 33 publications

(20 citation statements)

References 12 publications

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“…The mRNA expression of FGFR2, but not that of FGFR1, has been confirmed in primary-cultured rat hepatocytes (29), and the FGFR4 mRNA is not expressed in adult rat liver (30). In addition, a full-length FGFR2 (135 kDa) and an amino-terminal truncated FGFR2 (115 kDa) with a deleted first immunoglobulin-like loop and acidic domain have been described (9, 10), and it has been reported that both of these FGFR2 receptors have similar activities in FGF-1 binding and that these FGFR2 receptors are comparably activated by FGF-1 (31).…”

Section: Discussionmentioning

confidence: 94%

Identification of a 79-kDa Heparin-binding Fibroblast Growth Factor (FGF) Receptor in Rat Hepatocytes and Its Correlation with the Different Growth Responses to FGF-1 between Hepatocyte Subpopulations

Tanahashi

Suzuki²,

Imamura³

et al. 1996

Journal of Biological Chemistry

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We reported previously that the potency of heparinbinding fibroblast growth factor-1 (FGF-1) as a mitogen for rat hepatocytes in primary culture is as high as that of epidermal growth factor (EGF) and hepatocyte growth factor. To gain insight into the pathophysiological significance of FGF-1 in hepatocyte growth, we analyzed the cooperative mitogenicity of FGF-1 and EGF. Results from a nuclear labeling assay using [ I-FGF-1 to the nonstimulated hepatocyte surface indicated that the high affinity FGF receptors comprise two FGF receptors that differ in molecular mass (128 and 79 kDa). Furthermore, the 79-kDa receptor was preferentially down-regulated when the hepatocytes were stimulated with EGF or hepatocyte growth factor. These data suggest that the abundant expression of the 79-kDa FGF receptor on some populations of hepatocytes is involved in their lack of response to FGF-1. The 128-and 79-kDa FGF receptors were assigned as FGFR2 using an antibody specific to the ectodomain of FGFR2, whereas the 79-kDa receptor was not reactive to the antibody against the carboxyl terminus of FGFR2. This 79-kDa FGF receptor was not tyrosine-phosphorylated in response to FGF-1 stimulation, while the 128-kDa FGF receptor was recognized by anti-phosphotyrosine antibody under the same conditions. Also, the heterodimer of 79-and 128-kDa FGF receptors was less tyrosine-phosphorylated than the homodimer of 128-kDa FGF receptors. These data suggest that the 79-kDa FGF receptor inhibits the function of the 128-kDa FGF receptor through their heterodimerization. Thus, we surmise that the difference in response to FGF-1 between the cell populations of normal rat hepatocytes was caused by the different levels of the 79-kDa FGF receptor in each cell population.Various growth factors, including transforming growth factor-␣ (TGF-␣), 1 epidermal growth factor (EGF), and hepatocyte growth factor (HGF), have been identified as potent hepatotrophic factors in primary-cultured hepatocytes (1-3). In agreement with the consequence in vitro, TGF-␣ (which acts through the EGF receptor) and HGF may contribute to the proliferation of liver parenchymal cells during regeneration in vivo (1, 2). We previously reported that the mitogenic activity of heparin-binding fibroblast growth factor-1 (FGF-1) in rat hepatocytes is comparable to that of EGF and HGF in vitro (4,5). In addition, Kan et al. (6) reported that the expression of FGF-1 mRNA is immediately induced in the remnant of rat liver after partial hepatectomy, prior to the induction of TGF-␣ and HGF mRNAs (7,8). These observations suggest that FGF-1 also promotes the growth of liver parenchymal cells during liver regeneration; however, the significance of FGF-1 in the proliferation of liver parenchymal cells has remained unknown. In this study, we examined the contribution of two potent mitogens, FGF-1 and EGF, to hepatocyte growth in vitro and found that the simultaneous addition of FGF-1 and EGF had a spatiotemporal additive effect upon DNA synthesis. These results suggest that the mitogenicity of ...

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Section: Discussionmentioning

confidence: 94%

Identification of a 79-kDa Heparin-binding Fibroblast Growth Factor (FGF) Receptor in Rat Hepatocytes and Its Correlation with the Different Growth Responses to FGF-1 between Hepatocyte Subpopulations

Tanahashi

Suzuki²,

Imamura³

et al. 1996

Journal of Biological Chemistry

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“…A splice variant of FGFR3 lacking both the signal peptide and the transmembrane domain has been detected in the nucleus in both normal and transformed breast epithelial cells (24). Furthermore, a hypoglycosylated, intracellular isoform of FGFR1 has been observed in embryonic tissues (34), and splice variants of FGFR1 and FGFR4 lacking the signal peptide and first immunoglobulin-like domain, with an intracellular localization, have been predicted (16,17).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Signaling and Morphological Transformation by a Membrane-Localized Derivative of the Fibroblast Growth Factor Receptor 3 Kinase Domain†

Webster

Donoghue

1997

Molecular and Cellular Biology

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Fibroblast growth factor (FGF) receptors (FGFRs) are membrane-spanning tyrosine kinase receptors that mediate regulatory signals for cell proliferation and differentiation in response to FGFs. We have previously determined that the Lys6503Glu mutation in the activation loop of the kinase domain of FGFR3, which is responsible for the lethal skeletal dysplasia thanatophoric dyplasia type II (TDII), greatly enhances the ligand-independent kinase activity of the receptor. Here, we demonstrate that expression of this construct induces a c-fos promoter construct approximately 10-fold but does not lead to proliferation or morphological transformation of NIH 3T3 cells. In contrast, the isolated kinase domain of activated FGFR3, targeted to the plasma membrane by a myristylation signal, is able to stimulate c-fos expression by 40-fold, induce proliferation of quiescent cells, and morphologically transform fibroblasts. This result suggests that the extracellular and transmembrane domains of FGFRs exert a negative regulatory influence on the activity of the kinase domain. Targeting of the activated kinase domain to either the cytoplasm or the nucleus does not significantly affect biological signaling, suggesting that signals from FGFR3 resulting in mitogenesis originate exclusively from the plasma membrane. Furthermore, our novel observation that expression of a highly activated FGFR3 kinase domain is able to morphologically transform fibroblasts suggests that dysregulation of FGFR3 has the potential to play a role in human neoplasia.Fibroblast growth factor (FGF) receptors (FGFRs) are high-affinity membrane-spanning receptors for FGFs. FGFRs are normally catalytically inactive in the absence of FGF ligands. The binding of FGF to the extracellular domain of FGFRs, in the presence of heparan sulfate proteoglycans, induces the dimerization of two receptor molecules, allowing transphosphorylation of tyrosines within the activation loop of the intracellular tyrosine kinase domains. Activation loop phosphorylation greatly enhances the ability of FGFRs to autophosphorylate as well as to phosphorylate substrates which transmit biological signals into the cell leading to cell proliferation, differentiation, angiogenesis, or embryogenesis (4,11,21,23). Although growth factor receptor-mediated signaling has traditionally been assumed to initiate from the plasma membrane, FGF-induced cell proliferation requires prolonged exposure to ligand (63), during which activated FGFRs relocalize to the perinuclear and/or nuclear compartments of the cell (35,43,44).Point mutations in different domains of three of the four highly related FGFRs have been identified as causing human developmental abnormalities, including skeletal and cranial malformation syndromes (38,40,58). Recent work suggests that the biochemical mechanism underlying these syndromes is ligand-independent activation of the FGFR tyrosine kinase activity (58), and this constitutive signal transduction is postulated to cause premature and abnormal maturation of the affected long bo...

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“…To examine the role of FGF signaling during chicken cardiogenesis in vivo, we have constructed replication-defective retroviral expression vectors capable of altering (i) levels of FGFR or (ii) the functional properties of its receptor. Since multiple subtypes have been documented for both FGF (20) and the FGFR (21,22), targeting of all subtypes in vivo is currently difficult to achieve. A truncated mutant of FGFR1 lacking its C-terminal kinase domain forms heterodimers with all known FGFR subtypes and effectively inhibits signal transduction in Xenopus oocytes and early-stage embryos (23,24), transgenic mice (25), and L6 cells (23).…”

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confidence: 99%

Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development.

Mima

Ueno

Fischman

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

171

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In In bird embryos, cardiac myocytes are derived from mesoderm lateral to Hensen's node (1, 2). Soon after gastrulation starts, these cells become committed to a myocyte lineage (3), begin to express muscle-specific genes (4, 5), and exhibit rhythmic contractile activity several hours later (Hamburger-Hamilton stage 10) (6, 7). The functioning myocytes proliferate actively early in development, but mitotic activity decreases later in embryogenesis and is completely lost after birth (8 MATERIALS AND METHODSRetroviral Vectors. The retroviruses used for the present study are replication-defective variants based on the spleen necrosis virus (26). Although the truncated FGFR1 inhibits FGF signaling (23)(24)(25), neither the population of dimeric receptors containing recombinant FGFR1 nor the level of FGFR1 mRNA can be monitored in individual cells in vivo. To identify cells expressing viral transgenes, the vectors were designed to coexpress the bacterial ,B-galactosidase (13-gal) gene lacZ and the FGFR1 sequence (Fig. 1). To equivalently express both FGFR1 and ,B-gal from dicistronic messages, the vector contained an internal ribosome entry sequence (IRES) derived from the 5' noncoding region of the encephalomyocarditis virus genome (28) between the FGFR1 and lacZ genes. An Xba I-Nco I fragment of pLZIC2 (29) encoding an IRES was inserted into pCXLp-(30); this was designated pCXIL. The Xba I-Sst I fragment of pCXIL encoding the IRES and 5' lacZ and a Sst I-Sal I fragment of pMC1871 (Pharmacia) were coligated into pSN(31) and designated pSNIZ. After removal of the poly(A) signal from FGFR1, full-length and truncated FGFR1 of pSVcFR and pSVcTR (23) were transferred into the Xba I site of pSNIZ, and these vectors were designated pSNFRIZ and pSNAFRIZ, respectively. The construct encoding AFGFR1 in antisense orientation has been termed pSNaFRIZ. By using a packaging cell line, D17.2G, we generated replication-defective virions as described (27). Viral propagation, proof of helper virus-free stocks, and the evidence for clonality in studies of myocardial development have Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor;

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Cloning, expression and tissue distribution of the gene encoding rat fibroblast growth factor receptor subtype 4

Cited by 33 publications

References 12 publications

Identification of a 79-kDa Heparin-binding Fibroblast Growth Factor (FGF) Receptor in Rat Hepatocytes and Its Correlation with the Different Growth Responses to FGF-1 between Hepatocyte Subpopulations

Identification of a 79-kDa Heparin-binding Fibroblast Growth Factor (FGF) Receptor in Rat Hepatocytes and Its Correlation with the Different Growth Responses to FGF-1 between Hepatocyte Subpopulations

Enhanced Signaling and Morphological Transformation by a Membrane-Localized Derivative of the Fibroblast Growth Factor Receptor 3 Kinase Domain†

Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development.

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