Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FLG/FGFRI gene, encoding a receptor for members of the FGF family, is located at 8p11.2-p12. It is amplified, overexpressed, and not grossly rearranged in the MDA-MB-134 breast carcinoma cell line, whereas other genes from the pericentromeric 8p region are not amplified. The FGF4/HSTFI gene, located at 11q13, is also amplified with a substantial portion of the 11q13 region, but is not overexpressed in MDA-MB-134 cells. In this cell line, amplified sequences constitute a large homogeneously staining region (HSR) which is part of a marker chromosome containing chromosome 8 and chromosome 11 sequences. Using probes for the FGF4/HSTFI and the FLG/FGFRI genes in fluorescence chromosomal in situ hybridization, we show that the HSR contains de novo fused and amplified 11q13 and 8p11-p12 sequences associated in a complex structure containing approximately the same number of FGF4 and FGFRI genes. The significance of this genetic abnormality for MDA-MB-134 cells, and for breast carcinogenesis in general, is unknown, but may underlie a particular type of oncogene activation.
...
PMID:Fusion and amplification of two originally non-syntenic chromosomal regions in a mammary carcinoma cell line. 138 61

In an attempt to verify the nature of amplification events at band q13 on chromosome 11 we surveyed the amplification status of ten molecular markers specific for this region (GSTP, SEA, D11S97, D11S146, BCLI, PRADI/CCNDI, HST/FGF4, INT2/FGF3, EMSI, and DIIS833E) in a panel of 389 primary breast carcinoma DNA samples. Eighty-eight tumors (23%) showed at least one of these markers amplified, but in a majority of the cases amplification encompassed more than one of the tested loci. Our data confirm that amplicons at 11q13 can cover large portions of DNA and are consistent with the existence of several cores of amplification. One important core seems to be, as previously described, centered around PRADI/CCNDI; 57 tumors (14.7%) showed amplification at PRADI/CCNDI either alone (one tumor) or along with amplification of BCLI or INT2/FGF3. The level of amplification of PRADI/CCNDI sometimes exceeded that of surrounding markers. Three additional amplification events occurring independently of amplification of PRADI/CCNDI were also detected. Centromeric to BCLI, probes to DIIS97, and DIIS146 detected amplification in 60 tumors (15.4%) and were often the only amplified markers. Telomeric to INT2/FGF3, DIIS833E was found amplified alone in ten tumors, and it was the most amplified marker in another six cases. At a shorter distance of INT2/FGF3, EMSI was the only amplified marker in two tumors, with a level of amplification that could exceed that of PRADI/CCNDI and DIIS833E. Our data thus suggest the existence of four independent amplified regions within band 11q13 in breast cancer.
...
PMID:Patterns of DNA amplification at band q13 of chromosome 11 in human breast cancer. 750 99

The murine fibroblast growth factor receptor 2 (FGFR2) and keratinocyte growth factor receptor (KGFR) are two products of the same gene which display distinct binding specificities. We and others have shown that a major structural element underlying this functional divergence is a variable 50 amino acids long region constituting the C-terminal half of the third immunoglobulin (Ig)-like domain of the receptor. This region of the two receptors is encoded by two distinct exons which are alternatively used in cells of different tissues and origin. To further investigate the role of this confined variable region in determining ligand binding specificity we have generated a chimeric molecule between FGFR1 and KGFR where the variable segment of KGFR replaces the homologous region in FGFR1. Binding studies as well as chemical crosslinking of radiolabeled ligands revealed that the recombinant FGFR1/KGFR chimera has retained the binding affinity to acidic FGF and FGF4 (hst/kfgf) but lost the capacity to bind basic FGF (bFGF). This chimeric receptor bound keratinocyte growth factor (KGF), however, with significantly lower affinity as compared with KGFR. High affinity binding of KGF was acquired only when also domain 2 in this chimera was replaced by its homologous domain from FGFR2. These results demonstrate that ligand binding and specificity involves multiple receptor elements which are located at both Ig-like domain 2 and 3 of FGF receptors.
...
PMID:Multiple structural elements determine ligand binding of fibroblast growth factor receptors. Evidence that both Ig domain 2 and 3 define receptor specificity. 768 32

FGF6 is structurally very similar to the other members of the FGF gene family, and particularly to the FGF4 gene, which was instrumental in its isolation. Its longest open reading frame encodes a 208 amino acid residues long protein, both in man and in the mouse. It is expressed as a 4.8 kb transcript in skeletal muscle. In developing muscle, expression starts at the myotomal stage and culminates in differentiated fetal muscle masses. In culture, FGF6 protein is mitogenic and has a transforming capacity for fibroblasts. It represses the terminal differentiation of myoblasts. Action of FGF6 could be mediated by the FGFR4 receptor, which binds FGF6 and whose gene is also expressed in developing skeletal muscle.
...
PMID:The human and mouse fibroblast growth factor 6 (FGF6) genes and their products: possible implication in muscle development. 819 50

The development of calvarial bones is tightly co-ordinated with the growth of the brain and needs harmonious interactions between different tissues within the calvarial sutures. Premature fusion of cranial sutures, known as craniosynostosis, presumably involves disturbance of these interactions. Mutations in the homeobox gene Msx2 as well as the FGF receptors cause human craniosynostosis syndromes. Our histological analysis of mouse calvarial development demonstrated morphological differences in the sagittal suture between embryonic and postnatal stages. In vitro culture of mouse calvaria showed that embryonic, but not postnatal, dura mater regulated suture patency. We next analysed by in situ hybridisation the expression of several genes, which are known to act in conserved signalling pathways, in the sagittal suture during embryonic (E15-E18) and postnatal stages (P1-P6). Msx1 and Msx2 were expressed in the sutural mesenchyme and the dura mater. FGFR2(BEK), as well as Bmp2 and Bmp4, were intensely expressed in the osteogenic fronts and Bmp4 also in the mesenchyme of the sagittal suture and in the dura mater. Fgf9 was expressed throughout the calvarial mesenchyme, the dura mater, the developing bones and the overlying skin, but Fgf4 was not detected in these tissues. Interestingly, Shh and Ptc started to be expressed in patched pattern along the osteogenic fronts at the end of embryonic development and, at this time, the expression of Bmp4 and sequentially those of Msx2 and Bmp2 were reduced, and they also acquired patched expression patterns. The expression of Msx2 in the dura mater disappeared after birth. <P> FGF and BMP signalling pathways were further examined in vitro, in E15 mouse calvarial explants. Interestingly, beads soaked in FGF4 accelerated sutural closure when placed on the osteogenic fronts, but had no such effect when placed on the mid-sutural mesenchyme. BMP4 beads caused an increase in tissue volume both when placed on the osteogenic fronts and on the mid-sutural area, but did not effect suture closure. BMP4 induced the expression of both Msx1 and Msx2 genes in sutural tissue, while FGF4 induced only Msx1. We suggest that the local application of FGF on the osteogenic fronts accelerating suture closure in vitro, mimics the pathogenesis of human craniosynostosis syndromes in which mutations in the FGF receptor genes apparently cause constitutive activation of the receptors. Taken together, our data suggest that conserved signalling pathways regulate tissue interactions during suture morphogenesis and intramembranous bone formation of the calvaria and that morphogenesis of mouse sagittal suture is controlled by different molecular mechanisms during the embryonic and postnatal stages. Signals from the dura mater may regulate the maintenance of sutural patency prenatally, whereas signals in the osteogenic fronts dominate after birth.
...
PMID:FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. 947 22

We disrupted the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene by introducing a neo cassette into the IIIc ligand binding exon and by deleting a genomic DNA fragment encoding its transmembrane domain and part of its kinase I domain. A recessive embryonic lethal mutation was obtained. Preimplantation development was normal until the blastocyst stage. Homozygous mutant embryos died a few hours after implantation at a random position in the uterine crypt, with collapsed yolk cavity. Mutant blastocysts hatched, adhered, and formed a layer of trophoblast giant cells in vitro, but after prolonged culture, the growth of the inner cell mass stopped, no visceral endoderm formed, and finally the egg cylinder disintegrated. It follows that FGFR2 is required for early postimplantation development between implantation and the formation of the egg cylinder. We suggest that FGFR2 contributes to the outgrowth, differentiation, and maintenance of the inner cell mass and raise the possibility that this activity is mediated by FGF4 signals transmitted by FGFR2. The role of early FGF signaling in pregastrulation development as a possible adaptation to mammalian (amniote) embryogenesis is discussed.
...
PMID:Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. 956 Feb 32

Satellite cells are the myogenic precursors in postnatal muscle and are situated beneath the myofiber basement membrane. We previously showed that fibroblast growth factor 2 (FGF2, basic FGF) stimulates a greater number of satellite cells to enter the cell cycle but does not modify the overall schedule of a short proliferative phase and a rapid transition to the differentiated state as the satellite cells undergo myogenesis in isolated myofibers. In this study we investigated whether other members of the FGF family can maintain the proliferative state of the satellite cells in rat myofiber cultures. We show that FGF1, FGF4, and FGF6 (as well as hepatocyte growth factor, HGF) enhance satellite cell proliferation to a similar degree as that seen with FGF2, whereas FGF5 and FGF7 are ineffective. None of the growth factors prolongs the proliferative phase or delays the transition of the satellite cells to the differentiating, myogenin(+) state. However, FGF6 retards the rapid exit of the cells from the myogenin(+) state that routinely occurs in myofiber cultures. To determine which of the above growth factors might be involved in regulating satellite cells in vivo, we examined their mRNA expression patterns in cultured rat myofibers using RT-PCR. The expression of all growth factors, excluding FGF4, was confirmed. Only FGF6 was expressed at a higher level in the isolated myofibers and not in the connective tissue cells surrounding the myofibers or in satellite cells dissociated away from the muscle. By Western blot analysis, we also demonstrated the presence of FGF6 protein in the skeletal musle tissue. Our studies therefore suggest that the myofibers serve as the main source for the muscle FGF6 in vivo. We also used RT-PCR to analyze the expression patterns of the four tyrosine kinase FGF receptors (FGFR1-FGFR4) and of the HGF receptor (c-met) in the myofiber cultures. Depending on the time in culture, expression of all receptors was detected, with FGFR2 and FGFR3 expressed only at a low level. Only FGFR4 was expressed at a higher level in the myofibers but not the connective tissue cell cultures. FGFR4 was also expressed at a higher level in satellite cells compared to the nonmyogenic cells when the two cell populations were released from the muscle tissue and fractionated by Percoll density centrifugation. The unique localization patterns of FGF6 and FGFR4 may reflect specific roles for these members of the FGF signaling complex during myogenesis in adult skeletal muscle.
...
PMID:Gene expression patterns of the fibroblast growth factors and their receptors during myogenesis of rat satellite cells. 1089 1

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
...
PMID:Attenuation of FGF signalling in mouse beta-cells leads to diabetes. 1113 Jul 26

Fibroblast growth factors (FGFs) comprise a large family of multifunctional, heparin-binding polypeptides that show diverse patterns of interaction with a family of receptors (FGFR1 to -4) that are subject to alternative splicing. FGFR binding specificity is an essential mechanism in the regulation of FGF signaling and is achieved through primary sequence differences among FGFs and FGFRs and through usage of two alternative exons, IIIc and IIIb, for the second half of immunoglobulin-like domain 3 (D3) in FGFRs. While FGF4 binds and activates the IIIc splice forms of FGFR1 to -3 at comparable levels, it shows little activity towards the IIIb splice forms of FGFR1 to -3 as well as towards FGFR4. To begin to explore the structural determinants for this differential affinity, we determined the crystal structure of FGF4 at a 1.8-A resolution. FGF4 adopts a beta-trefoil fold similar to other FGFs. To identify potential receptor and heparin binding sites in FGF4, a ternary FGF4-FGFR1-heparin model was constructed by superimposing the FGF4 structure onto FGF2 in the FGF2-FGFR1-heparin structure. Mutation of several key residues in FGF4, observed to interact with FGFR1 or with heparin in the model, produced ligands with reduced receptor binding and concomitant low mitogenic potential. Based on the modeling and mutational data, we propose that FGF4, like FGF2, but unlike FGF1, engages the betaC'-betaE loop in D3 and thus can differentiate between the IIIc and IIIb splice isoforms of FGFRs for binding. Moreover, we show that FGF4 needs to interact with both the 2-O- and 6-O-sulfates in heparin to exert its optimal biological activity.
...
PMID:Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis. 1148 33

To identify amplified oncogenes involved in hepatocellular carcinomas (HCC), we applied a genomic DNA microarray spotted with 57 oncogenes to 20 HCCs. Aberrations in DNA copy number also were analyzed by comparative genomic hybridization (CGH) using an aliquot of DNA samples. In 5 of 20 HCCs, only 6 oncogenes (CCND1, FGF3/FGF4, SAS/CDK4, TERC, MET, and MYC) were amplified, whereas in the remaining 15 tumors no oncogenes were amplified. A comparison of DNA microarray and conventional CGH analyses showed that, although 5 of 6 amplified oncogenes shown by microarray were located in chromosomal regions shown by CGH to have increased DNA copy numbers, not all genes located in such chromosomal regions were affected. One of the amplified oncogenes (SAS/CDK4) was found in a chromosomal region that was undetected by CGH. We, therefore, conclude that amplification of the oncogenes examined in this series is not directly implicated in hepatocellular carcinogenesis.
...
PMID:Examination of oncogene amplification by genomic DNA microarray in hepatocellular carcinomas: comparison with comparative genomic hybridization analysis. 1167 33


1 2 3 4 5 6 7 8 Next >>

---