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 Fgf8 gene is expressed in developing limb and craniofacial structures, regions known to be important for growth and patterning of the mouse embryo. Although Fgf8 is alternatively spliced to generate at least 7 secreted isoforms that differ only at their mature amino terminus, the biological significance of these multiple isoforms is not known. In this report, we demonstrate that multiple FGF-8 isoforms are present at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alternatively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c activate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also efficiently activates 'c' splice form of FGFR2. No activity could be detected for recombinant or cell expressed FGF-8a. Furthermore, none of the isoforms tested interact efficiently with 'b' splice forms of FGFR1-3, or the 'c' splice form of FGFR1. These results indicate that the FGF-8b and FGF-8c isoforms, produced by ectodermally derived epithelial cells, interact with mesenchymally expressed fibroblast growth factor receptors. FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.
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PMID:FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. 858 74

Emerging evidence suggests that Fgf8, a recently identified member of the fibroblast growth factor family, plays an important role in outgrowth and patterning of the face, limbs, and central nervous system of the vertebrate embryo. We report the mapping of FGF8 to human chromosome 10q25-q26, using Southern blot analyses of genomic DNAs from rodent/human somatic cell hybrid lines. Apert, Crouzon, Jackson-Weiss, and Pfeiffer syndromes are craniosynostoses genetically linked in part to 10q25-q26 and are associated with point mutations in the extracellular domain of FGFR2. Given the assignment to the same chromosomeal band(s) as FGFR2 and the probable ligand-receptor relationship of the gene products of FGF8 and FGFR2, we hypothesize that some cases of these craniosynostoses linked to 10q25-q26 that do not have mutations in FGFR2 may involve mutations in FGF8.
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PMID:Assignment of FGF8 to human chromosome 10q25-q26: mutations in FGF8 may be responsible for some types of acrocephalosyndactyly linked to this region. 859 89

Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.
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PMID:Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes. 933 70

FGFR2 is a membrane-spanning tyrosine kinase that serves as a high affinity receptor for several members of the fibroblast growth factor (FGF) family. To explore functions of FGF/FGFR2 signals in development, we have mutated FGFR2 by deleting the entire immunoglobin-like domain III of the receptor. We showed that murine FGFR2 is essential for chorioallantoic fusion and placenta trophoblast cell proliferation. Fgfr2(DeltaIgIII/DeltaIgIII) embryos displayed two distinct defects that resulted in failures in formation of a functional placenta. About one third of the mutants failed to form the chorioallantoic fusion junction and the remaining mutants did not have the labyrinthine portion of the placenta. Consequently, all mutants died at 10-11 days of gestation. Interestingly, Fgfr2(DeltaIgIII/DeltaIgIII) embryos do not form limb buds. Consistent with this defect, the expression of Fgf8, an apical ectodermal factor, is absent in the mutant presumptive limb ectoderm, and the expression of Fgf10, a mesenchymally expressed limb bud initiator, is down regulated in the underlying mesoderm. These findings provide direct genetic evidence that FGF/FGFR2 signals are absolutely required for vertebrate limb induction and that an FGFR2 signal is essential for the reciprocal regulation loop between FGF8 and FGF10 during limb induction.
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PMID:Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. 943 95

To elucidate the roles of fibroblast growth factors (FGF) in tooth development, we have analyzed the expression patterns of fibroblast growth factor receptors (FGFR) in mouse teeth by in situ hybridization and studied the effects of FGF-2, -4, -8, and -9 on cell proliferation in vitro by local application with beads on isolated dental mesenchymes. mRNAs of FGFR-1, -2, and -3 were localized by probes specific for the alternative splice variants IIIb and IIIc. The expression patterns of FGFR1 -2, and -3 were completely different, and the two splicing variants of FGFR1 and 2 exhibited different expression domains. FGFR4 was not expressed in the developing teeth. The IIIb splice forms of FGFR1 and -2 were expressed in the dental epithelium during morphogenesis. 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. Both splice forms of FGFR3 were expressed in dental papilla mesenchyme. None of the FGF-receptors was detected in the primary enamel knot, the putative signaling center regulating tooth morphogenesis. This may explain the fact that enamel knot cells do not proliferate, although they express intensely mitogenic FGFs. Beads releasing FGF-2, -4, -8, or -9 proteins stimulated cell proliferation in cultured dental mesenchymes. These data, together with our earlier data on FGF expression [Kettunen and Thesleff (1998): Dev Dyn 211:256-268] suggest that FGF-8 and -9 mediate epithelial-mesenchymal interactions during tooth initiation. During advancing morphogenesis FGF-3, -4, and -9 may act both on mesenchyme and epithelium. Finally, the intense expression of FGFR1 in odontoblasts and ameloblasts and FGFR2 IIIb in ameloblasts suggests that FGFs participate in regulation of their differentiation and/or secretory functions.
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PMID:Responsiveness of developing dental tissues to fibroblast growth factors: expression of splicing alternatives of FGFR1, -2, -3, and of FGFR4; and stimulation of cell proliferation by FGF-2, -4, -8, and -9. 966 89

Low levels of p27Kip1 in primary prostate cancer specimens have been shown to be associated with higher rates of disease recurrence and poor rates of disease-free survival in patients with localized disease. In this study, we provide the first direct evidence showing that dihydrotestosterone (DHT), a major proliferation regulator of prostate cancer, can down-regulate p27Kip1 and stimulate cyclin-dependent kinase-2 (CDK2) activity in established prostate cancer cell lines. We investigated the cooperative effects of DHT and epidermal growth factor (EGF) on the proliferation of androgen-responsive MDA PCa 2a and MDA PCa 2b prostate cancer cells. DHT and EGF each stimulated proliferation of these cells, but exposure of the cells to DHT and EGF together stimulated greater proliferation. Stimulation of cell proliferation by DHT and/or EGF was associated with increased CDK2 activity and a decreased level of p27Kip1. There seems to be a positive feedback stimulation loop between androgen-induced gene transcription and EGF-stimulated signal transduction, as one could stimulate the synthesis of the receptors for the other. Dual blockade of androgen receptor function with the antiandrogen hydroxyflutamide and EGF receptor superfamily-mediated signal transduction with the anti-EGF receptor monoclonal antibody C225 and the anti-HER2 receptor monoclonal antibody Herceptin significantly enhanced growth inhibition of the MDA PCa 2a cells. Our results demonstrate the importance of counteracting both androgen receptors and EGF receptors in the development of novel therapies for prostate cancer.
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PMID:Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. 1047 2

Fibroblast growth factors (FGFs) mediate essential cellular functions by activating one of four alternatively spliced FGF receptors (FGFRs). To determine the mechanism regulating ligand binding affinity and specificity, soluble FGFR1 and FGFR3 binding domains were compared for activity. FGFR1 bound well to FGF2 but poorly to FGF8 and FGF9. In contrast, FGFR3 bound well to FGF8 and FGF9 but poorly to FGF2. The differential ligand binding specificity of these two receptors was exploited to map specific ligand binding regions in mutant and chimeric receptor molecules. Deletion of immunoglobulin-like (Ig) domain I did not effect ligand binding, thus localizing the binding region(s) to the distal two Ig domains. Mapping studies identified two regions that contribute to FGF binding. Additionally, FGF2 binding showed positive cooperativity, suggesting the presence of two binding sites on a single FGFR or two interacting sites on an FGFR dimer. Analysis of FGF8 and FGF9 binding to chimeric receptors showed that a broad region spanning Ig domain II and sequences further N-terminal determines binding specificity for these ligands. These data demonstrate that multiple regions of the FGFR regulate ligand binding specificity and that these regions are distinct with respect to different members of the FGF family.
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PMID:Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity. 1057 49

Among the members of the fibroblast growth factor receptor family the FGFR4 has demonstrated strong dependence on heparin-like material for its activation by fibroblast growth factors. We have produced and characterized a recombinant human FGFR4 extracellular domain (FGFR4ed), in order to study its biochemical properties in isolated conditions. The FGFR4ed was expressed in an insect cell system and purified from the culture medium by Ni(2+)-affinity and gel filtration chromatography. Pure FGFR4ed was tested for FGF- and heparin-binding by covalent crosslinking experiments and by biosensor analysis. In solution, FGFR4ed formed complexes with acidic FGF (FGF-1) and basic FGF (FGF-2), both in the presence and absence of heparin. Immobilized FGFR4 also bound FGF-8 besides FGF-1 and FGF-2. Furthermore, heparin alone induced receptor oligomerization on the surface of the receptor coupled chip. Thus, the recombinant FGFR4ed revealed properties described for the cellular form of this receptor and can be used for interaction studies.
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PMID:Production and characterization of the extracellular domain of recombinant human fibroblast growth factor receptor 4. 1073 64

Steroid hormones play key roles in regulating cell proliferation and differentiation in targeting tissues. However, in advanced cancers, the steroid hormone regulation is frequently attenuated through a yet unknown mechanism even in the presence of functional steroid hormone receptors. We investigate the functional role of tyrosine phosphorylation signaling in the hormone-refractory growth of human prostate tumors. Initial studies demonstrate that the androgen-responsive phenotype of human prostate cancer cells associates with a low phosphotyrosine (p-Tyr) level of ErbB-2, which is regulated by cellular prostatic acid phosphatase (PAcP), a protein tyrosine phosphatase. In prostate cancer cells, the p-Tyr level, but not the protein level, of ErbB-2 inversely correlates with the androgen-responsiveness of cell proliferation. Androgen-stimulated cell growth concurs with a down-regulation of cellular PAcP, an elevated p-Tyr level of ErbB-2, and the activation of mitogen-activated protein kinases. Furthermore, only the ErbB-2 inhibitor AG 879, but not the EGFR inhibitor AG 1478, abolishes androgen-induced cell proliferation. Forced expression of ErbB-2 can also attenuate androgen promotion of cell growth. Data taken collectively conclude that in human prostate cancer cells, the tyrosine phosphorylation of ErbB-2 regulated by cellular PAcP plays a key role in regulating androgen-mediated proliferation signaling. Oncogene (2000).
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PMID:Interaction between protein tyrosine phosphatase and protein tyrosine kinase is involved in androgen-promoted growth of human prostate cancer cells. 1085 Oct 66

FGF-8 is a mitogenic growth factor, which is widely expressed during embryonic development but only at a very low level in adult tissues. Alternative splicing of the human FGF-8 gene potentially allows coding for 4 protein isoforms (a, b, e, f), which differ in their transforming capacity. The FGF-8 isoforms preferentially activate the receptors FGFR1IIIc, FGFR2IIIc, FGFR3IIIc and FGFR4. FGF-8 is over-expressed in human breast and prostate cancers. Expression has also been found in RT-PCR studies of human ovarian and testicular cancers. The present study was undertaken to examine which FGF-8 isoforms are expressed in ovarian cancer and whether FGF-8 receptors are also expressed. Specimens from 5 normal human ovaries and 51 ovarian tumors (1 benign tumor, 8 borderline malignancies, 42 malignant tumors of different histopathological types) were studied by RT-PCR and immunohistochemistry. FGF-8 isoform b was expressed in all ovarian tumors and in all 7 ovarian-cancer cell lines studied. Isoform a was co-expressed in 9 malignant ovarian tumors. FGF-8 mRNA was not detected by RT-PCR of 3 normal ovary samples. Immunohistochemical staining localized FGF-8 protein to cancer cells. In general, the increased intensity of FGF-8 staining was associated with loss of differentiation within the tumors (Bowker's test, p = 0.37). FGF-8 staining of surface epithelium observed on 2 normal ovaries was very faint. RT-PCR showed that FGFR1IIIc, FGFR2IIIc and FGFR4 were the FGF-8 receptors expressed in normal ovaries and in ovarian tumors. FGF-8 receptor immunoreactivity was preferentially found in normal ovary surface epithelium and tumor cells but also in some stromal cells. Collectively, our results show that ovarian cancers of a wide variety of histological types expressing receptors for FGF-8 have acquired the capacity of expressing FGF-8. This suggests that FGF-8 has an important role in ovarian tumorigenesis.
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PMID:Expression of fibroblast growth factor (FGF)-8 isoforms and FGF receptors in human ovarian tumors. 1107 39


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