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)

A novel protein tyrosine kinase not related to pp60c-src, designated as N-PTK, has recently been found in neonatal rat brain. In the present study, the enzyme was purified further by heparin-Sepharose column chromatography, and identified as a monomer protein with a Mr of 47 K and a pI of 7.0 by two-dimensional gel electrophoresis. The enzyme was found to phosphorylate purified pp60c-src at a tyrosine residue(s). The major phosphorylation site was shown by alpha-chymotryptic peptide mapping to be in the carboxy terminal V8 protease fragment (V2), but to be different from the autophosphorylation site, Tyr-416. The phosphorylation significantly suppressed pp60c-src activity with enolase as a substrate. These findings strongly suggest that N-PTK is a specific kinase that phosphorylates pp60c-src and regulates its function in the cell.
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PMID:Identification of a novel protein tyrosine kinase that phosphorylates pp60c-src and regulates its activity in neonatal rat brain. 245 63

The c-fes proto-oncogene product is expressed predominantly in hematopoietic cells of the myeloid lineage and has been implicated in the regulation of myeloid differentiation. The c-fes locus encodes a 93-kDa protein tyrosine kinase (p93c-fes) that possesses several structural features characteristic of the cytoplasmic class of protein tyrosine kinases, including a consensus sequence for autophosphorylation surrounding Tyr-713 and a src homology 2 (SH2) domain. To assess the effect of each of these potential regulatory sites on p93c-fes protein tyrosine kinase activity, we specifically deleted the c-fes SH2 domain using the polymerase chain reaction and replaced Tyr-713 with phenylalanine by oligonucleotide-directed mutagenesis (Y713F mutant). The resulting mutants were expressed in Escherichia coli and assayed for changes in protein tyrosine kinase activity using an immune complex kinase assay. Both mutations produced a marked decrease in the rate and extent of autophosphorylation and phosphorylation of the model substrate, enolase. To test whether the c-fes SH2 domain could interact with the autophosphorylated kinase domain, the SH2 domain was expressed as a fusion protein with glutathione S-transferase and immobilized on glutathione-agarose. The recombinant c-fes SH2 domain precipitated p93c-fes as readily as a monoclonal antibody. Binding of the SH2 domain to p93c-fes was completely dependent upon autophosphorylation, as a kinase-defective mutant of p93c-fes was not precipitated by the SH2 domain. High-affinity binding was also observed with recombinant SH2 domains from v-src and v-fps, raising the possibility of protein-protein interactions between various members of the cytoplasmic PTK family. These results indicate that the c-fes SH2 domain and consensus autophosphorylation site (Tyr-713) play major roles in the positive regulation of p93c-fes tyrosine kinase activity, possibly through intramolecular interaction.
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PMID:Regulation of the human c-fes protein tyrosine kinase (p93c-fes) by its src homology 2 domain and major autophosphorylation site (Tyr-713). 768 63

The met proto-oncogene is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF is a multifunctional cytokine that stimulates mitogenesis, motility, invasion, and tubulogenesis of a spectrum of epithelial and endothelial cells in culture. Using a chimeric receptor (CSF-MET), containing the extracellular domain of the colony stimulating factor-1 (CSF-1) receptor fused to the transmembrane and intracellular domain of the Met receptor, we have previously demonstrated that activation of the Met kinase domain is sufficient to mediate the motility, invasion and morphogenic signals of HGF/SF in Madin-Darby canine kidney epithelial cells (MDCK). In this study we have analyzed the role of tyrosine phosphorylation of the Met receptor in the transmission of these signals by site-directed mutagenesis of specific tyrosine residues. Mutation of two tyrosine residues (tyrosine 1234 and tyrosine 1235), involved in activation of the catalytic activity of the kinase, abrogates the biological activity of the chimera. In addition, we have identified a single noncatalytic tyrosine residue (tyrosine 1356) in the carboxyl terminus of the Met receptor, that is essential for the biological activity of the chimeric receptor. Mutation of tyrosine 1356 to a nonphosphorylatable phenylalanine residue does not affect the exogenous kinase activity of the receptor toward enolase, but it impairs the ability of the mutant protein to associate with the adaptor protein Grb2, and MDCK cells expressing this mutant fail to scatter, invade, and form branching tubules in response to CSF-1. These results support a crucial role for tyrosine 1356 in activation of signaling pathways involved in the biological activity of the Met receptor in response to HGF/SF.
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PMID:Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis. 796 92

Pheochromocytomas are rare tumours, with an incidence of 1-2 per million which arise from chromaffin cells of the adrenal medulla. They occur sporadically or as part of dominantly inherited cancer syndromes like multiple endocrine neoplasia 2 (MEN2A and 2B) and others. Continuous cell lines, not available so far, are essential tools for studies in these tumours. A continuous cell line (KNA) was established from a sporadic pheochromocytoma of the right adrenal gland of a 73-year-old woman. The KNA cells grow as suspensions of spheroids and show the morphological and immunocytochemical characteristics of neuronal chromaffin cells, such as neuroendocrine granules, and positive reactions to chromogranin- and related peptide-, neuron specific enolase and vasoactive intestinal peptide antibodies. Neurite-like processes are formed after addition of nerve growth factor. Chromosomal analyses revealed a diploid (46,XX,n = 50) to hypodiploid (43-45,XX,n = 15) karyotype. In hypodiploid metaphases most frequently #19, #17, #21 and #22 were missing. Chromosome arms 1p and 4q showed apparently consistent interstitial deletions: 6q, 8q, 13q and 22q showed clonal interstitial deletions. The cell line shows a heterozygous sequence variant TGC (cysteine) to TGG (tryptophan) in codon 611 in exon 10 of the RET proto-oncogene. So far, PC-12, a rat adrenal pheochromocytoma, has been the only continuous pheochromocytoma cell line available. KNA represents the first report on a human continuous pheochromocytoma cell line, the first report of structural chromosome aberrations in pheochromocytomas and the first report of a RET mutation TGC to TGG in exon 10 of the RET proto-oncogene in a sporadic pheochromocytoma.
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PMID:First continuous human pheochromocytoma cell line: KNA. Biological, cytogenetic and molecular characterization of KNA cells. 1064 Jan 77

IL-2, first identified as a T cell growth factor, has been proven to activate many cell types including polymorphonuclear neutrophils (PMN3). However, the mechanisms involved in PMN activation, especially the signaling pathways used by the IL-2R, are currently unknown. Here we demonstrate that IL-2 has the ability to induce protein tyrosine kinases in human PMN, and we provide the first evidence that lyn kinase is activated and physically associated with MAP kinase/ERK1. Co-immunoprecipitation experiments with anti-IL-2Rbeta and Western blotting with anti-p53/56lym revealed that lyn protein was present in IL-2R precipitates and that the association of lyn with IL-2Rbeta was markedly elevated by IL-2 stimulation. Furthermore the activity of lyn kinase, evaluated by an in vitro kinase assay with enolase as a substrate, increased following IL-2 stimulation. Another important finding was that, upon IL-2 activation, MAPK/ERK1 was also phosphorylated in PMN. A direct association between lyn and ERK1 was initially demonstrated by co-immunoprecipitation/Western blotting and then definitively proven by the use of a GST-ERK1 fusion protein. We showed that ERK1 binds lyn only in IL-2 stimulated PMN, but not in unstimulated PMN. These results suggest that IL-2 can promote the association of lyn protein tyrosine kinase with IL-2Rbeta as well as the direct binding of MAPK/ERK1 to lyn. The signaling pathway utilized by human PMN in response to IL-2 may thus involve the association of lyn with IL-2Rbeta and the activation process also triggers the recruitment and activation of a specific ERK.
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PMID:IL-2 induces the association of IL-2Rbeta, lyn, and MAP kinase ERK-1 in human neutrophils. 1113 Nov 53

Activation of cAMP signaling pathway and its transcriptional factor cyclic AMP response element binding protein (CREB) and coactivator are key determinants of neuronal differentiation and plasticity. We show that nuclear fibroblast growth factor receptor-1 (FGFR1) mediates cAMP-induced neuronal differentiation and regulates CREB and CREB binding protein (CBP) function in alpha-internexin-expressing human neuronal progenitor cells (HNPC). In proliferating HNPC, FGFR1 was associated with the cytoplasm and plasma membrane. Treatment with dB-cAMP induced nuclear accumulation of FGFR1 and caused neuronal differentiation, accompanied by outgrowth of neurites expressing MAP2 and neuron-specific neurofilament-L protein and enolase. HNPC transfected with nuclear/cytoplasmic FGFR1 or non-membrane FGFR1(SP-/NLS), engineered to accumulate exclusively in the cell nucleus, underwent neuronal differentiation in the absence of cAMP stimulation. In contrast, FGFR1/R4, with highly hydrophobic transmembrane domain of FGFR4, was membrane associated, did not enter the nucleus and failed to induce neuronal differentiation. Transfection of tyrosine kinase-deleted dominant negative receptor mutants, cytoplasmic/nuclear FGFR1(TK-) or nuclear FGFR1(SP-/NLS)(TK-), prevented cAMP-induced neurite outgrowth. Nuclear FGFR1 localized in speckle-like domains rich in phosphorylated histone 3 and splicing factors, regions known for active RNA transcription and processing, and activated the neurofilament-L gene promoter. FGFR1(SP-/NLS) transactivated CRE, up-regulated phosphorylation and transcriptional activity of CREB and stimulated the activity of CBP several-fold. Thus, cAMP-induced nuclear accumulation of FGFR1 provides a signal that triggers molecular events leading to neuronal differentiation.
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PMID:cAMP-induced differentiation of human neuronal progenitor cells is mediated by nuclear fibroblast growth factor receptor-1 (FGFR1). 1261 30

Thiol proteins are important in cellular antioxidant defenses and redox signalling. It is postulated that reactive oxidants cause selective thiol oxidation, but relative sensitivities of different cell proteins and critical targets are not well characterized. We exposed Jurkat cells to H2O2 for 10 min and measured changes in reversibly oxidized proteins by labelling with iodoacetamidofluorescein and two-dimensional electrophoresis. At 200 microM H2O2, which caused activation of the MAP (mitogen-activated protein) kinase ERK (extracellular-signal-regulated kinase), growth arrest and apoptosis, relatively few changes were seen. A total of 28 spots were reversibly oxidized (increased labelling intensity) and 24 decreased. The latter included isoforms of peroxiredoxins 1 and 2, which were irreversibly oxidized. Oxidation of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was striking, and other affected proteins included glutathione S-transferase P1-1, enolase, a regulatory subunit of protein kinase A, annexin VI, the mitotic checkpoint serine/threonine-protein kinase BUB1beta, HSP90beta (heat-shock protein 90beta) and proteosome components. At 20 microM H2O2, changes were fewer, but GAPDH and peroxiredoxin 2 were still modified. Dinitrochlorobenzene treatment, which inhibited cellular thioredoxin reductase and partially depleted GSH, caused reversible oxidation of several proteins, including thioredoxin 1 and peroxiredoxins 1 and 2. Most changes were distinct from those with H2O2, and changes with H2O2 were scarcely enhanced by dinitrochlorobenzene. Relatively few proteins, including deoxycytidine kinase, nucleoside diphosphate kinase and a proteosome activator subunit, responded only to the combined treatment. Thus most of the effects of H2O2 were not linked to thioredoxin oxidation. Our study has identified peroxiredoxin 2 and GAPDH as two of the most oxidant-sensitive cell proteins and has highlighted how readily peroxiredoxins undergo irreversible oxidation.
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PMID:Proteomic detection of hydrogen peroxide-sensitive thiol proteins in Jurkat cells. 1580 6

We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature. In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma. This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.
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PMID:Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype. 1653 63

"Rhythmic palisading" is a striking histologic pattern infrequently encountered in a variety of central nervous system (CNS) tumors. We present the case of an infant with a large spinal cord lesion wherein all sampled tissue showed columnar arrangements of palisaded cells, typical of polar spongioblastoma. The tumor was briskly proliferative, focally necrotic, and variably expressed S100, glial fibrillary acidic protein, neuron specific enolase, and p53 by immunohistochemistry. Fluorescence in situ hybridization failed to reveal isochromosome 17q, EGFR amplification, or deletions of 1p, 19q, 22q11.2, 10q, or p16. Despite chemotherapy and decadron, he developed lesional necrosis and intracranial metastases and died less than 1 mo from presentation. This case illustrates polar spongioblastoma as a distinctive histologic pattern that can occur in embryonal CNS tumors. Discrimination of these rare aggressive lesions from other CNS tumors with focal palisaded architecture is crucial as the treatment and prognosis of the latter may differ significantly.
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PMID:Polar spongioblastoma of the spinal cord: a case report. 1680 41

The author reports a rare case of primary large cystic extragastrointestinal stromal tumor (eGIST) of the transverse mesocolon with genetic analyses of the c-kit and platelet-derived growth factor receptor-alpha (PDGFRA) genes. A 78-year-old man was found to have a large cystic tumor in the abdomen, and the tumor was resected. Grossly, the tumor was located in the transverse mesocolon, and cystic. Microscopically, the tumor consisted of epithelioid cells with atypia. Mitotic figures were noted in five of 50 high power fields. Immunohistochemically, the tumor cells were positive for KIT, CD34, PDGFRA, and vimentin, but negative for cytokeratins, neuron specific enolase, desmin, S100 protein, alpha-smooth muscle actin, p53 protein, HMB45, CD68, CEA, factor VIII-related antigen, chromogranin, and synaptophysin. Ki67 labeling was 5%. Genetically, the tumor showed a point mutation (GAC --> GTC) at codon 842 of exon 18 of the PDGFRA gene. Exon 12 of the PDGFRA gene and exons 9, 11, 13, and 17 of the c-kit gene showed no mutations. No recurrence is noted 3 years after the operation. This case shows that eGIST may occur in the transverse mesocolon.
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PMID:Primary extragastrointestinal stromal tumor of the transverse mesocolon without c-kit mutations but with PDGFRA mutations. 1877 14


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