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

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

The four members of the fibroblast growth factor receptor (FGFR) family are cell-surface membrane-spanning tyrosine kinase receptors involved in a wide spectrum of biologic processes. Much evidence also indicates that mutations in FGFR genes result in several craniosynostotic disorders and chondrodysplasias, and that changes in qualitative and quantitative FGFR expression profiles are implicated in tumor induction or progression. Here, we describe a precise and reliable competitive PCR-based assay to evaluate human FGFR1-4 gene expression. A single multispecific synthetic competitive template was designed to amplify FGFR1-4 homologous stretches and constructed to contain FGFR1/FGFR2/FGFR3/FGFR4/GAPDH tandemly arranged forward and reverse primers that allow competition for cDNA-specific primer annealing. The housekeeping GAPDH transcript was utilized as a reference for comparing the expression profiles of different RNA pools. The assay herein described allows the comparison of relative FGFR expression levels, both within a single RNA pool and among multiple RNA pool samples. The major advantages of such a PCR-based approach are its ability to obtain unbiased FGFR mRNA expression patterns and to detect transcripts present in low copy number. Qualitative and semiquantitative analyses of the FGFR1-4 transcript repertoire in mesenchymal- and epithelial-derived primary cell cultures and cell lines demonstrated the utility of such a method to investigate the FGFR1-4 functional role in FGF signal transduction.
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PMID:A competitive PCR-based method to measure human fibroblast growth factor receptor 1-4 (FGFR1-4) gene expression. 1144 8

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.
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PMID:Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis. 1148 33

Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases encoded by four closely related genes. FGFR 1, 2, and 3 have a number of isoforms derived by alternative splicing, alternative initiation and exon switching; however, FGFR4 has been reported to encode a single intact receptor with three extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and a split intracellular kinase. Here we describe a novel C-terminally truncated soluble isoform of FGFR4 expressed by human epithelial breast cancer MCF-7 cells. This isoform results from failure of splicing of intron 4 resulting in an mRNA species that encodes an in-frame premature stop codon. Cells transfected with the corresponding cDNA containing intron 4 express a truncated releasable protein that is identified in conditioned media. This soluble FGFR4 isoform (sFGFR4) abrogates the effect of FGF-1-induced MAPK phosphorylation and PRL gene activation. These findings represent the first description of an endogenous soluble C-terminally truncated FGFR4 isoform with FGF modulatory properties.
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PMID:A soluble dominant negative fibroblast growth factor receptor 4 isoform in human MCF-7 breast cancer cells. 1154 53

We have reported that normal human salivary gland-derived epithelial cells exclusively express keratinocyte growth factor receptor (KGFR). In the process of malignant transformation of human salivary gland tumors, KGFR gene expression disappeared concomitantly with the de novo expression of the fibroblast growth factor receptor 1 (FGFR1) and FGFR4 genes. In the present study, we introduced wild-type KGFR cDNA or chimeric KGFR/FGFR1 cDNA, which encoded the extracellular domain of KGFR and the intracellular domain of FGFR1, into the HSY human salivary adenocarcinoma cell line. The KGFR tyrosine kinase suppressed the activity of FGF receptor substrate 2 (FRS2) and inhibited the growth of HSY by inducing differentiation and apoptosis in vitro and in vivo. Our results provided significant insight into the mechanism of KGFR tumor suppression and suggest that KGFR gene therapy might be a viable method of inhibiting human salivary adenocarcinoma growth.
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PMID:Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis. 1156 60

Heparan sulfates (HS) play an important role in the control of cell growth and differentiation by virtue of their ability to modulate the activities of heparin-binding growth factors, an issue that is particularly well studied for fibroblast growth factors (FGFs). HS/heparin co-ordinate the interaction of FGFs with their receptors (FGFRs) and are thought to play a critical role in receptor dimerization. Biochemical and crystallographic studies, conducted mainly with FGF-2 or FGF-1 and FGF receptors 1 and 2, suggests that an octasaccharide is the minimal length required for FGF- and FGFR-induced dimerization and subsequent activation. In addition, 6-O-sulfate groups are thought to be essential for binding of HS to FGFR and for receptor dimerization. We show here that oligosaccharides shorter than 8 sugar units support activation of FGFR2 IIIb by FGF-1 and interaction of FGFR4 with FGF-1. In contrast, only relatively long oligosaccharides supported receptor binding and activation in the FGF-1.FGFR1 or FGF-7.FGFR2 IIIb setting. In addition, both 6-O- and 2-O-desulfated heparin activated FGF-1 signaling via FGFR2 IIIb, whereas neither one stimulated FGF-1 signaling via FGFR1 or FGF-7 via FGFR2 IIIb. These findings indicate that the structure of HS required for activating FGFs is dictated by the specific FGF and FGFR combination. These different requirements may reflect the differences in the mode by which a given FGFR interacts with the various FGFs.
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PMID:Differential effects of heparin saccharides on the formation of specific fibroblast growth factor (FGF) and FGF receptor complexes. 1171 10

Endocrine tumors (ETs) of the digestive system produce several growth factors including acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), which are thought to be involved in the growth of tumor cells and in the proliferation of tumor stromal cells. Their actions depend on binding to four specific receptors--FGFR1, FGFR2, FGFR3, and FGFR4--whose distribution in normal endocrine cells and related tumors of the gastroenteropancreatic (GEP) system has previously been examined. Formalin-fixed, paraffin-embedded normal tissues and 60 well-characterized GEP endocrine tumors were immunostained using specific antibodies directed against various GEP hormones, aFGF, FGFR1, FGFR2, FGFR3, and FGFR4. Acidic FGF immunoreactivity (IR) was found in gut EC cells; FGFR1 immunoreactivity in rare duodenal endocrine cells and in pancreatic A cells; FGFR2 immunoreactivity in gastric and duodenal G cells, pancreatic B cells, and rectal EC cells; FGFR3 immunoreactivity in duodenal G cells; and FGFR4 immunoreactivity in rectal L cells and in pancreatic B, PP, and A cells. Immunoreactivity for at least one of the four FGFRs was found in all tumors, independently of FGFR expression in the putative cell of origin. EC cell tumors, which were all positive for aFGF, were found to express at least three different FGFRs. FGFRs also were localized in the stromal cells of all the tumors examined. The tumor stroma was more abundant in EC cell tumors than in other types of neoplasms. The results suggest that aFGF-FGFR interaction may be involved in the modulation of normal endocrine cell functions and in the regulation of tumor growth and stromal proliferation of EC cell carcinoids.
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PMID:Immunohistochemical detection of fibroblast growth factor receptors in normal endocrine cells and related tumors of the digestive system. 1175 58

It is estimated that up to one in five individuals develop pituitary gland tumors. Despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development remain largely unknown. We report the identification of a novel pituitary tumor-derived, N-terminally truncated isoform of FGF receptor-4 (ptd-FGFR4). The corresponding mRNA results from alternative transcription initiation and encodes a polypeptide that lacks a signal peptide and the first two extracellular Ig-like domains. ptd-FGFR4 has a distinctive cytoplasmic residence, is constitutively phosphorylated, and is transforming in vitro and in vivo. Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease.
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PMID:Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. 2623 43

Expression analysis of genes encoding components of the phosphotyrosine signaling system by cDNA array hybridization revealed elevated levels of FGFR4 transcripts in several mammary carcinoma cell lines. In the FGFR4 gene transcript from MDA-MB-453 mammary carcinoma cells, a G to A conversion was discovered that results in the substitution of glycine by arginine at position 388 in the transmembrane domain of the receptor. The Arg(388) allele was also found in cell lines derived from a variety of other tumor types as well as in the germ-line of cancer patients and healthy individuals. Analysis of three geographically separated groups indicated that it occurs in approximately 50% of the human population. Investigation of the clinical data of 84 breast cancer patients revealed that homo- or heterozygous carriers of the Arg(388) allele had a significantly reduced disease-free survival time (P = 0.01) within a median follow-up of 62 months. Moreover, the FGFR4 Arg(388) allele was associated with early lymph node metastasis and advanced tumor-node-metastasis (TNM) stage in 82 colon cancer patients. Consistent with this finding, MDA-MB-231 mammary tumor cells expressing FGFR4 Arg(388) exhibited increased motility relative to cells expressing the FGFR4 Gly(388) isotype. Our results support the conclusion that the FGFR4 Arg(388) allele represents a determinant that is innocuous in healthy individuals but predisposes cancer patients for significantly accelerated disease progression.
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PMID:Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. 1183 May 41

Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of endocrine cell hormonal and proliferative properties, and FGFR4 is differentially expressed in normal and neoplastic pituitary. We therefore examined the functionally important cis-DNA elements and multiprotein complexes implicated in the cooperative control of expression of the human FGFR4 gene in pituitary cells. Using deletional mapping, we defined a 214-bp (-115/+99) promoter that was functional in pituitary GH4 and PRL 235 cells. Overlapping 40- to 50-bp fragments of this minimal promoter were examined by EMSA. Interestingly, fragment C (-64/-26) included potential binding sites for the hematopoietic zinc finger-containing transcription factor Ikaros (Ik) flanked by binding sites for Sp and Ets-type factors. DNA binding by Ik, Sp, and Ets-like factors was confirmed by oligonucleotide competition and supershifting with specific antibodies. Transcriptional regulation of FGFR4 by Ik was demonstrated by cotransfection of Ik1 with or without Sp1 or Ets overexpression and by disruption of the Ik binding site. Although both Ets-1 and Sp1 overexpression stimulated promoter activity, mutation of the Ik-binding site completely eliminated the Ik1 effect. Specific Ik expression was identified by Western blotting of pituitary GH4 and PRL235 cells and localized in primary mouse hormone-producing anterior pituitary cells by immunocytochemistry. Our findings point to a new role for Ik outside the hematopoietic system and suggest a novel transcriptional contribution with Ets and Sp1 in regulation of FGFR4 in the pituitary.
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PMID:Fibroblast growth factor receptor 4 is a target for the zinc-finger transcription factor Ikaros in the pituitary. 1198 Oct 41

Fibroblast growth factor receptor (FGFR) signalling is important in the initiation and regulation of osteogenesis. Although mutations in FGFR1, 2, and 3 genes are known to cause skeletal deformities, the expression of FGFR4 in bony tissue remains unclear. We have investigated the expression pattern of FGFR4 in the neonatal mouse calvaria and compared it to the expression pattern in cultures of primary osteoblasts. Immunohistochemistry demonstrated that FGFR4 was highly expressed in rudimentary membranous bone and strictly localised to the cellular components (osteoblasts) between the periosteal and endosteal layers. Cells in close proximity to the newly formed osteoid (preosteoblasts) also expressed FGFR4 on both the endosteal and periosteal surfaces. Immunocytochemical analysis of primary osteoblast cultures taken from the same cranial region also revealed high levels of FGFR4 expression, suggesting a similar pattern of cellular expression in vivo and in vitro. RT-PCR and Western blotting for FGFR4 confirmed its presence in primary osteoblast cultures. These results suggest that FGFR4 may be an important regulator of osteogenesis with involvement in preosteoblast proliferation and differentiation as well as osteoblast functioning during intramembranous ossification. The consistent expression of FGFR4 in vivo and in vitro supports the use of primary osteoblast cultures for elucidating the role of FGFR4 during osteogenesis.
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PMID:Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures. 1214 39


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