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)

We previously identified pituitary tumor-derived fibroblast growth factor receptor 4 (ptd-FGFR4), an alternatively transcribed N-terminally truncated cytoplasmic receptor isoform. Unlike wild-type FGFR4, ptd-FGFR4 facilitates cell transformation and results in pituitary tumor formation in transgenic mice. To investigate differences in the tumorigenic properties of FGFR4 and ptd-FGFR4, we examined their abilities to modulate cell adhesiveness. Introduction of ptd-FGFR4 into GH4 pituitary cells or NIH 3T3 fibroblasts resulted in significant reduction in cell adhesion to a collagen IV matrix compared with FGFR4- or empty vector-transfected cells. This adhesive difference was evident in the absence or presence of FGF stimulation. Furthermore, treatment with beta1-integrin neutralizing antibody markedly reduced adhesiveness in FGFR4-transfected cells but had little effect on the depressed adhesiveness of ptd-FGFR4-transfected cells. Unlike wild-type FGFR4, ptd-FGFR4 does not associate with neural cell-adhesion molecule (NCAM). Cells expressing FGFR4 demonstrate membranous N-cadherin with a noninvasive growth pattern identical to control GH4 cells when injected into immunodeficient mice. In contrast, ptd-FGFR4-expressing cells develop invasive tumors in vivo with marked loss of N-cadherin that localizes to the cytoplasm. Consistent with these changes, beta-catenin expression was diminished and its interaction with N-cadherin was disrupted in the presence of ptd-FGFR4, but both were intact in the presence of wild-type FGFR4. These data highlight the importance of membrane-anchored FGFR4 in assembling a multiprotein FGFR4 complex with NCAM and N-cadherin playing pivotal functions in maintaining normal cell adhesion. Disruption of distinct NCAM/N-cadherin proadhesive complexes by a tumor-derived FGFR4 isoform provides a novel mechanism beyond ligand independence that explains the pathobiology of proliferative and infiltrative but nonmetastatic neoplasms.
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PMID:Pituitary tumor-derived fibroblast growth factor receptor 4 isoform disrupts neural cell-adhesion molecule/N-cadherin signaling to diminish cell adhesiveness: a mechanism underlying pituitary neoplasia. 1523 74

Although FGF signaling promotes myoblast proliferation and represses myogenic differentiation, one of the FGF receptors (FGFR), FGFR4, is expressed mainly in mature skeletal muscle. Disruption of FGFR4 signaling interrupts chick limb muscle formation. To determine the developmental regulation of FGFR4 expression, we compared the transcriptional control and action of FGFR4 in myoblasts and myotubes. We identified higher FGFR4 expression in differentiated myotubes than precursor myoblasts. FGFR4 promoter activity was localized within a region 115 bp upstream of the transcription start site. Overlapping fragments of this promoter displayed a distinct difference when compared by electromobility shift assay (EMSA) using nuclear extracts from myoblasts and myotubes. While fragments B (-95/-56) and C (-65/-26) formed specific complexes in both cell types, these complexes were consistently more intense in myotubes than myoblasts. These complexes were efficiently competed by an Sp-type oligonucleotide and were supershifted by Sp1 and by Sp3 antibodies. Deletions of the Sp-binding sites in fragment B (-95/-56) confirmed their critical contribution to promoter activity. Moreover, Sp1 expression correlated with FGFR4-expression in myotubes. To determine whether FGFR4 expression regulates myoblast differentiation, we infected a soluble dominant-negative FGFR4-containing adenovirus into these cells. This significantly impeded Erk1/2 phosphorylation and differentiation of myoblasts into MHC-expressing myotubes. Our findings point to distinct transcriptional regulation and action for FGFR4 in differentiating skeletal muscle cells.
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PMID:Distinct transcriptional control and action of fibroblast growth factor receptor 4 in differentiating skeletal muscle cells. 1546 29

Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of differentiating and proliferative actions. FGFR4 is expressed mainly in lung, kidney, pancreas, spleen, and developing muscle. FGFR4 was found to be overexpressed in some human malignancies, where it has been implicated in their pathogenesis. Recently, FGFR4 was found to be overexpressed in pediatric rhabdomyosarcomas, based on cDNA microarray analysis. Using Northern blotting, reverse transcription-polymerase chain reaction, and Western blotting, we classified four human rhabdomyosarcoma-derived cell lines based on their relative expression of FGFR4. We defined a 214 bp (-115/+99) promoter that functioned as a minimal promoter and examined cis-DNA elements implicated in the control of expression of the FGFR4 gene in these cells. Overlapping 40- to 50-bp fragments of the minimal promoter were examined by electrophoretic mobility shift assay using nuclear extracts from cell lines with high (HS729-1015) or low (HS729-1016) FGFR4 expression. Fragment C (-65/-26) formed specific complexes with nuclear extracts from both cell lines. Fragment B (-95/-56), however, formed distinct complexes mainly with the high FGFR4-expressing HS729-1015 cells. Both fragments yielded complexes that were competed by an Sp oligonucleotide and supershifted by Sp1 and by Sp3 antibodies. Transfection of Sp1 but not Sp3 efficiently activated FGFR4 promoter activity, an effect that was significantly more pronounced in the HS729-1015 cell line than in the low FGFR4-expressing HS729-1016 cell line. Deletion of each of the two Sp-binding sites in fragments B and C resulted in loss of promoter activity. In particular, deletion of the 5' Sp-binding site in fragment B was associated with the greatest loss of activity. Sp1 protein expression correlated with FGFR4 expression in cell lines and primary human rhabdomyosarcomas. Furthermore, transfection of Sp1 and methylation inhibition was effective in inducing the endogenous FGFR4 gene in HS729-1015 cells. Our findings point to Sp1 as an important contributor to FGFR4 transcriptional control and elucidate a potential mechanism for the heterogeneous expression of FGFR4 in neoplasms derived from the same cell lineage.
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PMID:Sp1-mediated transcriptional control of fibroblast growth factor receptor 4 in sarcomas of skeletal muscle lineage. 1547 66

Cell fate and morphogenesis within the embryo is dependent upon secreted molecules that transduce signals between neighboring tissues. Reciprocal mesenchymal-epithelial interactions have proven essential during branching morphogenesis and cell differentiation within the lung; however, the interactions that result in lung specification from the foregut endoderm, prior to lung bud formation, are poorly understood. In this study, we investigate the tissue requirements and signals necessary for specification of a pulmonary cell fate using embryo tissue explants. We show that NKX2.1, an early transcription factor crucial for lung development, is expressed in the ventral foregut endoderm shortly after albumin and Pdx1, early markers of the liver and pancreas lineages, respectively. Similar to hepatic specification, direct contact of cardiac mesoderm with ventral endoderm is required to induce in vitro expression of NKX2.1 and downstream lung target genes including surfactant protein C and Clara cell secretory protein. In the absence of cardiac mesoderm, ventral foregut endoderm explants respond to exogenous fibroblast growth factor (FGF) 1 and FGF2 in a dose-dependent manner, with lower concentrations activating liver specific genes and higher concentrations activating lung specific genes. This signaling appears to be instructive, as the prospective dorsal midgut endoderm, which predominantly gives rise to the intestinal tract, is competent to respond to FGFs by inducing NKX2.1. Furthermore, the temporal expression and selective inhibition of FGF receptors 1 and 4 present within the endoderm implies that signaling through FGFR4 is involved in specifying lung versus liver. Together, the findings suggest that a concentration threshold of FGFs emanating from the cardiac mesoderm are involved in patterning the foregut endoderm.
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PMID:Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. 1557 1

Overexpression of fibroblast growth factors (FGFs) has been implicated in prostate carcinogenesis. FGFs function via their high-affinity interactions with receptor tyrosine kinases, FGFR1-4. Expression of FGFR1 and FGFR2 in prostate cancer (CaP) was not found to be associated with clinical parameters. In this report, we further investigated for abnormal FGFR expression in prostate cancer and explore their significance as a potential target for therapy. The expression levels of FGFR3 and FGFR4 in CaP were examined and corroborated to clinical parameters. FGFR3 immunoreactivity in benign prostatic hyperplasia (BPH) and CaP (n=26 and 57, respectively) had similar intensity and pattern. Overall, FGFR4 expression was significantly upregulated in CaP when compared to BPH. A significant positive correlation between FGFR4 expression and Gleason score was noted: Gleason score 7-10 tumours compared to BPH (P<0.0001, Fisher's exact test), Gleason score 4-6 tumours compared to BPH (P<0.0004), and Gleason 7-10 compared to Gleason 4-6 tumours (P<0.005). FGFR4 overexpression was associated with an unfavourable outcome with decreased disease-specific survival (P<0.04, log rank test). FGF-induced signalling is targeted using soluble FGF receptor (sFGFR), potent inhibitor of FGFR function. We have previously shown that sFGFR expression via a replication-deficient adenoviral vector (AdlllcRl) suppresses in vitro FGF-induced signalling and function in human CaP DU145 cells. We tested the significance of inhibiting FGF function along with conventional therapeutic modalities in CaP, and confirmed synergistic effects on in vitro cell growth (proliferation and colony formation) by combining sFGFR expression and treatment with either Paclitaxel (Taxol) or gamma-irradiation. In summary, our data support the model of FGF system as valid target for therapy in CaP.
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PMID:Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer. 1565 58

Medullary thyroid cancer is frequently an aggressive form of carcinoma for which there are currently no effective forms of systemic therapy. These carcinomas arise as a result of activating mutations in the RET proto-oncogene transmembrane tyrosine kinase receptor. We, therefore, examined the potential efficacy of the tyrosine kinase inhibitor STI571 on the growth of human TT medullary cancer cells in vitro and in xenografted severe combined immunodeficiency mice. Treatment with STI571 resulted in inhibition of RET phosphorylation, cell proliferation, tumor growth and invasiveness. Based on the profile of expression of fibroblast growth factor receptors (FGFR), we examined the effects of FGFR tyrosine kinase inhibition using the small molecule FGFR inhibitor PD173074. This inhibitor resulted in abrogation of fibroblast growth factor-1-mediated FGFR4 phosphorylation in TT cells, an effect that was accompanied by significant arrest of cell proliferation and tumor growth in vivo. Moreover, the combination of STI571 and PD173074 resulted in greater suppression of cell proliferation in vitro and tumor control in vivo than that achieved with either agent alone. These data highlight RET and FGFR4 as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable medullary thyroid cancers.
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PMID:Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. 1570 6

The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. A variety of human skeletal dysplasias have been linked to specific point mutations in FGFR1, FGFR2 and FGFR3 leading to severe impairment in cranial, digital and skeletal development. Gain of function mutations in FGFRs were also identified in a variety of human cancers such as myeloproliferative syndromes, lymphomas, prostate and breast cancers as well as other malignant diseases. The binding of FGF and HSPG to the extracellular ligand domain of FGFR induces receptor dimerization, activation and autophosphorylation of multiple tyrosine residues in the cytoplasmic domain of the receptor molecule. A variety of signaling proteins are phosphorylated in response to FGF stimulation including Shc, phospholipase-Cgamma, STAT1, Gab1 and FRS2alpha leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. The docking proteins FRS2alpha and FRS2beta are major mediators of the Ras/MAPK and PI-3 kinase/Akt signaling pathways as well as negative feedback mechanisms that fine-tune the signal that is initiated at the cell surface following FGFR stimulation.
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PMID:Cellular signaling by fibroblast growth factor receptors. 1586 30

Although many theories have attempted to explain the etiopathogenesis of premature cranial suture fusion, which results in craniosynostosis, recent studies have focused on the role of growth factors and receptors. Using a well-established model of cranial suture biology, the authors developed a novel approach to quantitatively analyze the gene expression profiles of candidate cranial suture growth factors and their receptors. We collected suture mesenchyme and adjacent osteogenic fronts from Sprague-Dawley rats at postnatal days 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 35. RNA was extracted from posterior frontal (PF) and sagittal (SAG) sutures, and reverse transcription-polymerase chain reaction (RT-PCR) was performed for cranial suture candidate cytokines BMP2, BMP3, BMP4, FGF-2, FGFR1, FGFR2, FGFR4, TGF-betaRI, TGF-betaRII, and TGF-betaRIII. The authors confirmed quantitative RT-PCR results with Southern and dot blot analyses. Suture growth factor and receptor expression levels changed significantly with time. Expression levels decreased toward baseline in the SAG suture by day 35. There was a marked difference in FGFR1, FGF-2, TGF-betaRI, and TGF-betaRII expression levels when comparing the fusing PF and nonfusing SAG sutures. Although FGF-2 ligand expression was low, FGF receptor 1 (FGFR1) levels were markedly elevated with a bimodal expression pattern in both PF and SAG similar to that of BMP2, BMP3, and BMP4. Although there were statistically significant differences in TGF-betaRI and TGF-betaRII expression in the PF and SAG sutures, TGF-betaRIII levels were unchanged. The authors report a novel approach to cranial suture growth factor/receptor profiling and confirm their results with standard analytic tools. The data confirm, quantify, and extend the results of previously published studies. By quantifying the gene expression profiles of normal cranial suture biology, we may begin to understand the aberrant growth factor cascades of craniosynostosis and devise targeted therapeutic interventions that can alter the course of this malady.
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PMID:Gene expression profiling in the rat cranial suture. 1591

The fibroblast growth factor (FGF) family is known to be involved in vertebrate eye development. However, distinct roles of individual FGF members during eye development remain largely elusive. Here, we show a detailed expression pattern of Fgf19 in chick lens development. Fgf19 expression initiated in the forebrain, and then became restricted to the distal portion of the optic vesicle abutting the future lens placode, where FGF receptor 4 (Fgfr4), a receptor for FGF19, was expressed. Fgf8, a positive regulator for L-Maf, was expressed in a portion of the optic vesicle. To examine the role of FGF19 signaling during early eye development, Fgf19 was misexpressed near the presumptive lens ectoderm; however, no alteration in the expression of lens marker genes was observed. Conversely, a secreted form of FGFR4 was misexpressed to inhibit an FGF19 signal, resulting in the induction of L-Maf expression. To further define the relationship between L-Maf and Fgf19, L-Maf misexpression was performed, resulting in ectopic induction of Fgf19 expression by Hamburger and Hamilton's stage 12/13. Furthermore, misexpression of Fgf8 induced Fgf19 expression in addition to L-Maf. These results suggest that FGF19-FGFR4 signaling plays a role in early lens development in collaboration with FGF8 signaling and L-Maf transcriptional system.
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PMID:FGF19-FGFR4 signaling elaborates lens induction with the FGF8-L-Maf cascade in the chick embryo. 1592 96

Although the detection of several components of the fibroblast growth factor (FGF) signaling pathway in human embryonic stem cells (hESCs) has been reported, the functionality of that pathway and effects on cell fate decisions are yet to be established. In this study we characterized expression of FGF-2, the prototypic member of the FGF family, and its receptors (FGFRs) in undifferentiated and differentiating hESCs; subsequently, we analyzed the effects of FGF-2 on hESCs, acting as both exogenous and endogenous factors. We have determined that undifferentiated hESCs are abundant in several molecular-mass isoforms of FGF-2 and that expression pattern of these isoforms remains unchanged under conditions that induce hESC differentiation. Significantly, FGF-2 is released by hESCs into the medium, suggesting an autocrine activity. Expression of FGFRs in undifferentiated hESCs follows a specific pattern, with FGFR1 being the most abundant species and other receptors showing lower expression in the following order: FGFR1 --> FGFR3 --> FGFR4 --> FGFR2. Initiation of differentiation is accompanied by profound changes in FGFR expression, particularly the upregulation of FGFR1. When hESCs are exposed to exogenous FGF-2, extracellular signal-regulated kinases are phosphorylated and thereby activated. However, the presence or absence of exogenous FGF-2 does not significantly affect the proliferation of hESCs. Instead, increased concentration of exogenous FGF-2 leads to reduced outgrowth of hESC colonies with time in culture. Finally, the inhibitor of FGFRs, SU5402, was used to ascertain whether FGF-2 that is released by hESCs exerts its activities via autocrine pathways. Strikingly, the resultant inhibition of FGFR suppresses activation of downstream protein kinases and causes rapid cell differentiation, suggesting an involvement of autocrine FGF signals in the maintenance of proliferating hESCs in the undifferentiated state. In conclusion from our data, we propose that this endogenous FGF signaling pathway can be implicated in self-renewal or differentiation of hESCs.
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PMID:Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells. 1595 29


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