Disease relevance of Fgfr1

• Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums [1].
• First, we employed the aphakia (ak) lens complementation system to show that Fgfr1 deficient embryonic stem (ES) cells were able to form a normal embryonic lens that maintains a normal pattern of crystallin gene expression [2].
• Development of the geniculate placode as well as the VIIth cranial ganglion is affected in Fgfr1 hypomorphs [3].
• Although FGFR1 is expressed by hepatic cell progenitors and adult nonparenchymal cells, ectopic expression is commonly observed in hepatoma cells [4].
• However, in diethylnitrosamine-treated mice, the chronic FGFR1 activity promoted an incidence of 44% adenomas at 4 months and 38% hepatocellular carcinoma at 8 months [4].

Psychiatry related information on Fgfr1

• In this article, we review the expression of FGFRs in human development, the phenotypes resulting from FGFR mutations, and recent data identifying pathways downstream of the activated receptors [5].
• Fibroblast growth factor receptor-1 expression in the cortex and hippocampus in Alzheimer's disease [6].

High impact information on Fgfr1

• Finally, we compare the PDGFRbeta and fibroblast growth factor receptor 1; each induces essentially identical IEGs in fibroblasts [7].
• Heparan sulfate-deficient mutants transfected to express a cloned mouse FGF receptor cDNA are not able to bind bFGF [8].
• The identification of FGFR1 as a co-receptor for AAV should provide new insights not only into its role in the life cycle of AAV, but also in the optimal use of AAV vectors in human gene therapy [9].
• Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth [10].
• Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism [11].

Chemical compound and disease context of Fgfr1

• We expressed dominant-negative FGFR2 (FGFR2-DN) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracycline-regulated expression systems [12].
• Chronic activity of ectopic type 1 fibroblast growth factor receptor tyrosine kinase in prostate epithelium results in hyperplasia accompanied by intraepithelial neoplasia [13].
• For adeno-associated virus type 2 (AAV2) infection, heparan sulfate proteoglycan is supposed as the primary receptor, and alphavbeta5 integrin and FGFR1 are reported to act as coreceptors [14].
• These results suggest that both apoptosis and differentiation are two processes that are simultaneously implicated in synostosis of the coronal suture in case of a FGFR-related craniosynostosis [15].
• Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia [16].

Biological context of Fgfr1

• Together the results demonstrate an essential role for Fgfr1 in patterning and morphogenesis of the telencephalon [17].
• Fgfr2 is expressed only in proliferating osteoprogenitor cells; the onset of differentiation is preceded by down-regulation of Fgfr2 and up-regulation of Fgfr1 [18].
• Furthermore, we found that morpholino knockdown of medaka fgf8 resulted in a phenotype identical to the fgfr1(hdf) mutant, suggesting that like its mouse counterpart, Fgf8 is a major ligand for Fgfr1 in medaka early embryogenesis [19].
• At early stages of embryogenesis, Fgfr1, Fgfr2, and several FGFs are critical for both the induction of the otic vesicle and the initial development of the sensory epithelium [20].
• Expression patterns of Twist and Fgfr1, -2 and -3 in the developing mouse coronal suture suggest a key role for twist in suture initiation and biogenesis [21].

Anatomical context of Fgfr1

• We show that Cre-mediated deletion of Fgfr1 in limb mesenchyme, beginning at a time point slightly after the first sign of initial budding, primarily affects formation of the first one or two digits [22].
• In the Fgfr1-deficient telencephalon, AP patterning is largely normal [17].
• Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak [23].
• Mice lacking Fgfr1, either in progenitor cells or in differentiated osteoblasts, showed increased bone mass as adults [24].
• To investigate the biological basis of FGFR signalling pathways in the developing calvarium we compared the expression patterns of Twist with those of Fgfr1, -2 and -3 in the fetal mouse coronal suture over the course of embryonic days 14-18, as the suture is initiated and matures [21].

Associations of Fgfr1 with chemical compounds

• Inhibiting FGFR1 signaling with SU5402, a FGFR1 tyrosine kinase inhibitor, reduced branching morphogenesis [25].
• Interaction of androgen-induced autocrine heparin-binding growth factor with fibroblast growth factor receptor on androgen-dependent Shionogi carcinoma 115 cells [26].
• Immunoprecipitation using multiple FGFR-1 antibodies followed by an in vitro tyrosine kinase activity assay enabled us to identify FGFR-1 as a 130-kDa phosphotyrosine-containing protein associated with the nuclear fraction of NIH 3T3 cells exposed to FGF-1 [27].
• Testosterone and FGF-2 increased the expression of FGFR-1 messenger RNA (mRNA) and, to a lesser extent, FGFR-3 mRNA, but down-regulated FGFR-2 mRNA in S115 cells [28].
• A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor [29].
• Bromodeoxyuridine labeling experiments demonstrate that FGFR1 is required for the proliferation of NPCs as well as generation of new neurons in the adult dentate gyrus (DG) [30].

Physical interactions of Fgfr1

• To determine the developmental requirements for Fgfr1-Frs signaling, we generated mice (Fgfr1(Delta)Frs/DeltaFrs) in which the Frs2/3-binding site on Fgfr1 is deleted [31].
• Despite the fact that we have observed inhibition of bFGF binding by the 18-mer phosphorothioate oligodeoxynucleotides for both the high and low affinity classes of bFGF receptor, the inhibition was sequence-selective only for the high affinity receptors [32].
• We have also demonstrated that a monoclonal antibody prepared against FGF receptor (R)-1 is able to co-precipitate Src-related proteins in lysates from FGF-1-treated NIH 3T3 cells [33].
• Using a receptor binding competition assay, Fgf3 was shown to bind with high affinity to the IIIb isoforms of Fgf receptor (FgfR) 1 and FgfR2 (ID50 = approximately 0.8 nM) and with a lower affinity to the IIIc variant of FgfR2 (ID50 = approximately 9 nM) [34].
• FGF-23 binds to the FGF receptor 3c, which is mainly expressed in opossum kidney cells, with high affinity [35].

Enzymatic interactions of Fgfr1

• Shp2 was able to dephosphorylate fibroblast growth factor receptor-induced phosphotyrosines on Spry both in vivo and in vitro [36].

Regulatory relationships of Fgfr1

• We also observed FGFR-1 associated with the nuclear fraction in FGFR-1-transfected L6 rat myoblasts, which are known to be refractive to exogenous FGF-1 and express relatively low levels of endogenous FGFR-1 [27].
• The IIIc splice form of FGFR1 was expressed both in epithelium and mesenchyme whereas FGFR2 IIIc was confined to the mesenchymal cells of the dental follicle [37].
• N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling [38].
• Moreover, suramin completely blocked androgen- or bFGF-induced accumulation of FGF receptor-1 mRNA [39].
• These effects require activation of an FGF tyrosine kinase receptor as they are blocked by transfection of a dominant negative mutant FGF receptor [40].

Other interactions of Fgfr1

• We show that FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast through redundant function of Fgfr1 and Fgfr2 [41].
• These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth [42].
• Like FGFR1 and FGFR3, it exists as two splice variants, IIIb and IIIc [43].
• An examination of fgf receptor gene expression indicated that all four receptors (fgfr-1 to fgfr-4) are expressed in postnatal lungs at varying levels [44].
• As Bmp7 is an established lens induction signal, this provides further evidence that Fgfr activity is important for lens induction [45].

Analytical, diagnostic and therapeutic context of Fgfr1

• Fgfr, Fgf and Bmp gene expression was localized to either the mesenchyme or the epithelium by PCR, and then measured over time by real time PCR after SU5402 treatment [25].
• The functional significance of FGFR1 was confirmed by submandibular gland organ culture [25].
• Binding of the intact fusion protein to FGF receptor 1 (FGFR1) on T cells was demonstrated by immunoprecipitation of the receptor bound to Fc-FGF-1 and by flow cytometry showing binding of fusion protein to T cells expressing FGFR1 [46].
• In addition, analysis by confocal immunofluorescence microscopy of quiescent and FGF-1-stimulated NIH 3T3 cells reveal a prominent perinuclear FGFR-1 staining pattern in the cells exposed to FGF-1 but not in the quiescent population [27].
• We have used both standard and whole-mount in situ hybridization techniques to analyze the temporal and spatial expression patterns of the murine fibroblast growth factor receptor-1 (FGFR-1) in order to help define the role of FGFs in the processes of gastrulation and segmentation [47].

References