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)

In Part IV of this review of placental pathology, reference is made to impaired maturation of the placenta under special clinical conditions. Foetal erythroblastosis is only of minor importance, in that context, today, while similar placental alterations may result from foetal hydrops of different genesis, including immunological causes. A detailed account is given of diabetic impairment of maturation together with possible placental diagnosis of diabetes. Cases of diabetes mellitus with concomitant EPH gestosis were found to be more strongly determined for placental differentiation by EPH gestosis. Reference, finally, is made to disturbed placental differentiation under conditions of EPH gestosis with or without concomitant impairment of intervillous circulation.
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PMID:[Pathology of the placenta. IV. Maturation disorders of the placenta under special clinical conditions]. 205 7

The cloning and sequencing of the oncogene of the avian erythroblastosis virus S13 is described. The oncogene, termed v-sea, was found to be another member of the protein-tyrosine kinase gene family. The oncogene was fused in frame with the retrovirus S13 envelope gene, thus generating a fusion protein with a structure resembling that of a growth factor receptor. Sequence comparisons revealed that the v-sea gene was most closely related to the insulin receptor family of protein-tyrosine kinases, the greatest similarity being with the human MET oncogene.
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PMID:The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family. 254 51

A region of the primary amino acid sequence of the epidermal growth factor receptor (EGF) protein-tyrosine kinase, which is involved in ATP binding, was identified using chemical modification and immunological techniques. EGF receptor was 14C-labelled with the ATP analogue 5'-p-fluorosulphonylbenzoyladenosine and from a tryptic digest a single radiolabelled peptide was isolated. The amino acid sequence was determined to be residues 716-724 and hence lysine residue 721 is located within the ATP-binding site. Antisera were elicited in rabbits to a synthetic peptide identical to residues 716-727 of the EGF receptor and the homologous sequence in v-erb B transforming protein from avian erythroblastosis virus. The affinity-purified antibodies precipitated human ECF receptor from A431 cells and placenta, and the v-erb B protein from erythroblasts. The antibodies inhibited EGF-stimulated receptor protein-tyrosine kinase autophosphorylation and phosphorylation of an exogenous peptide substrate containing tyrosine. The antibodies did not immunoprecipitate the transforming proteins pp60v-src or P120gag-abl or cAMP-dependent protein kinase, proteins which have homologous but not identical sequences surrounding the lysine residue within the ATP-binding site, nor did they react with the platelet-derived growth factor receptor. The antibodies had no effect on the kinase activity of purified v-abl protein in solution. The antibodies may therefore be a specific inhibitor of the tyrosine kinase of the EGF receptor.
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PMID:Antibodies to the ATP-binding site of the human epidermal growth factor (EGF) receptor as specific inhibitors of EGF-stimulated protein-tyrosine kinase activity. 301 11

The epidermal growth factor receptor, EGFR, has been implicated in cell transformation in both mammalian and avian species. The v-ErbB oncoprotein is an oncogenic form of the chicken EGFR. The tyrosine kinase activity of this oncoprotein is required for transformation, but no transformation-specific cellular substrates have been described to date. Recently activation of the ras signal transduction pathway by the EGFR has been shown to involve the Shc and Grb2 proteins. In this communication, we demonstrate that the Shc proteins are phosphorylated on tyrosine residues and are complexed with Grb2 and the chicken EGFR following ligand activation of this receptor. In fibroblasts and erythroid cells transformed by the avian erythroblastosis virus (AEV) strains H and ES4, the Shc proteins are found to be constitutively phosphorylated on tyrosine residues. The tyrosine-phosphorylated forms of the AEV strain H v-ErbB protein are found in a complex with Shc and Grb2, but the Shc proteins do not bind to the AEV strain ES4 v-ErbB protein. Mutant forms of the v-ErbB protein (in which several of the tyrosines that become autophosphorylated have been deleted by truncation) are unable to transform erythroid cells but can still transform fibroblasts. Analysis of cells transformed by one of these mutants revealed that the truncated v-ErbB protein could no longer bind to either Shc or Grb2, but this oncoprotein still gave rise to tyrosine-phosphorylated Shc proteins that complexed with Grb2 and led to activation of mitogen-activated protein (MAP) kinase. The results suggest that stable binding of Grb2 and Shc to the v-ErbB protein is not necessary to activate this signal transduction pathway and assuming that the mutant activate MAP kinase in erythroid cells in a manner similar to that of fibroblasts, that activation of this pathway is not sufficient to transform erythroid cells.
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PMID:Analysis of the role of the Shc and Grb2 proteins in signal transduction by the v-ErbB protein. 790 55

First member of Ets gene family was discovered a decade ago by studying avian erythroblastosis virus, E26. This virus encodes a tripartite protein gag-myb-ets with a molecular weight of 135 kDa. Subsequently, a series of cellular Ets genes were isolated (Ets-1, Ets-2, Erg, Elk-1, Sap-1, PEA-3, PU.1, Fli-1, Pok/Yan, Etv-1 etc.). These genes share sequence homology to E26 Ets gene (v-ets or viral ets). Ets genes are highly conserved in phylogenetically divergent species from Drosophila to man. Mammalian Ets genes are located on different chromosomes. Ets gene products are transcriptionally active sequence-specific DNA binding proteins and are differentially regulated. Ets genes are involved in certain chromosomal translocations leading to the formation of chimeric fusion proteins that are associated with certain leukemias and soft tissue cancers. Ets genes also have a role in T-cell development and molecular and genetic analysis of Down Syndrome patients have implicated the human Ets-2 and Erg genes in the disease. Down Syndrome afflicted patients have immunologic and thymic disorders as well as a greater risk for leukemic disease. Thus, Ets genes having homology to viral oncogenes, may be instrumental in regulating cellular growth and differentiation, as well as organismal development. Alteration of these genes and their products may cause deregulation of normal cell growth and differentiation and result in a disease.
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PMID:Ets oncogene family. 931 29

In immortalized cells of the erythroid lineage, the iron-regulatory protein (IRP) has been suggested to coregulate biosynthesis of the iron storage protein ferritin and the erythroid delta-aminolevulinate synthase (eALAS), a key enzyme in heme production. Under iron scarcity, IRP binds to an iron-responsive element (IRE) located in ferritin and eALAS mRNA leaders, causing a block of translation. In contrast, IRP-IRE interaction is reduced under high iron conditions, allowing efficient translation. We show here that primary chicken erythroblasts (ebls) proliferating or differentiating in culture use a drastically different regulation of iron metabolism. Independently of iron administration, ferritin H (ferH) chain mRNA translation was massively decreased, whereas eALAS transcripts remained constitutively associated with polyribosomes, indicating efficient translation. Variations in iron supply had minor but significant effects on eALAS mRNA polysome recruitment but failed to modulate IRP-affinity to the ferH-IRE in vitro. However, leukemic ebls transformed by the v-ErbA/v-ErbB-expressing avian erythroblastosis virus showed an iron-dependent reduction of IRP mRNA-binding activity, resulting in mobilization of ferH mRNA into polysomes. Hence, we analyzed a panel of ebls overexpressing v-ErbA and/or v-ErbB oncoproteins as well as the respective normal cellular homologues (c-ErbA/TRalpha, c-ErbB/EGFR). It turned out that v-ErbA, a mutated class II nuclear hormone receptor that arrests erythroid differentiation, caused the change in ferH mRNA translation. Accordingly, inhibition of v-ErbA function in these leukemic ebls led to a switch from iron-responsive to iron-independent ferH expression.
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PMID:Impaired ferritin mRNA translation in primary erythroid progenitors: shift to iron-dependent regulation by the v-ErbA oncoprotein. 1059 77

V-SEA is the transforming component of S13 Avian Erythroblastosis Retrovirus that causes erythroblastosis and anemia in chicken. Like all members in the family (MET, RON, SEA), its cytosolic domain possesses two tyrosine autophosphorylation sites in the tandemly arranged bidentate motif that serve as docking sites for SH2 domain-containing proteins. Here, we investigated phosphotyrosine-dependent activation of signaling pathways and their significance in V-SEA-induced transformation and/or proliferation. We demonstrated that V-SEA activates the PI3K-Akt signaling pathway primarily in Y557- and secondarily in Y564-dependent manner. V-SEA was also shown to induce the tyrosine phosphorylation of the Gab2 protein, leading to PI3K association and thus providing an alternative route for PI3K activation. On the other hand, activation of the Ras-ERK pathway is primarily via Y564 and secondarily via Y557. A dominant-negative form of Ras inhibited V-SEA-induced ERK phosphorylation in concentration dependent manner suggesting the importance of the Grb2-Ras signaling axis in V-SEA-induced ERK activation. The biological significance of activation of the PI3K-Akt and the Ras-ERK pathways in V-SEA-induced transformation was analysed in the V-SEA-RAT1 and V-SEA-3T3 cell lines by employing specific inhibitors, LY294002 and PD98059 compounds. Both the PD and LY compounds inhibited cell growth, but only the PD compound caused reversion of the transformed phenotype. In addition, both compounds inhibited focal colony formation by the transformants in soft agar. Thus, transformation by the V-SEA oncogene is a function of the concomitant activation of, at least, the PI3K-Akt and Ras-ERK signaling pathways that regulate cell growth and morphology.
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PMID:Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene. 1185 Jul 98

The tyrosine kinase receptor erbB2, also known in humans as Her2, is a member of the epidermal growth factor receptor (EGFR or erbB1) family, which also includes erbB3 and erbB4. The erbBs were discovered in an avian erythroblastosis tumor virus and exhibited similarities to human EGFR (Yarden and Sliwkowski, 2001). Her2/erbB2 is highly expressed in many cancer types. Its overexpression is correlated with a poor prognosis for breast and ovarian cancer patients. ErbB receptors bind to a family of growth factors, termed neuregulins/heregulin (NRG/HRG), which comprise NRG-1, -2, -3, and -4 and include multiple isoforms. ErbB2/Her2 is an orphan receptor that does not bind ligand alone but heterodimerizes with the other erbB receptors for NRG signaling. ErbB2 is expressed in multiple neuronal and non-neuronal tissues in embryos and adult animals, including the heart. Genetic data demonstrated that erbB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons. ErbB2/Her2-null mutant embryos of a trabeculation defect die before embryonic day (E) 11. To study its role at later stages of development, we generated a transgenic mouse line that specifically expresses the rat erbB2 cDNA in the heart under the control of the cardiac-specific alpha-myosin heavy chain promoter. When crossed into the null background, the expression of the rat erbB2 cDNA rescued the cardiac phenotype in the erbB2-null mutant mice that survive until birth but display an absence of Schwann cells and a severe loss of both motor and spinal sensory neurons. To study the role of erbB2 in the adult heart, we generated conditional mutant mice carrying a cardiac-restricted deletion of erbB2. These erbB2 conditional mutants exhibited multiple independent parameters of dilated cardiomyopathy, including chamber dilation, wall thinning, and decreased contractility. Interestingly, treatment of breast cancers overexpressing erbB2 with Herceptin (Trastuzumab), a humanized monoclonal antibody specific to the extracellular domain of erbB2, results in some patients developing cardiac dysfunction. The adverse effect is increased significantly in those patients who also receive the chemotherapeutical agent anthracycline. We found that erbB2-deficient cardiac myocytes are more susceptible to anthracycline-induced cytotoxicity. These results suggest that erbB2 signaling in the heart is essential for the prevention of dilated cardiomyopathy. These lines of mice provide models with which to elucidate the molecular and cellular mechanisms by which erbB2 signaling regulates cardiac functions. These mice also will provide important information for devising strategies to mitigate the cardiotoxic effects of Herceptin treatment, allowing for the potential expanded use of this drug to treat all cancers overexpressing erbB2.
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PMID:Essential roles of Her2/erbB2 in cardiac development and function. 1474 94

Friend virus is an acutely oncogenic retrovirus that causes erythroblastosis and polycythemia in mice. Previous studies suggested that the Friend virus oncoprotein, gp55, constitutively activates the erythropoietin receptor (EPOR), causing uncontrolled erythroid proliferation. Those studies showed that gp55 confers growth factor independence on an interleukin-3 (IL-3)-dependent cell line (Ba/F3) when the EPOR is coexpressed. Subsequently, we showed that a truncated form of the stem-cell kinase receptor (sf-STK) is required for susceptibility to Friend disease. Given the requirement for sf-STK, we sought to establish the in vivo significance of gp55-mediated activation of the EPOR. We found that the cytoplasmic tyrosine residues of the EPOR, and signal transducer and activator of transcription-5 (STAT5), which acts through these sites, are not required for Friend virus-induced erythroblastosis. The EPOR itself was required for the development of erythroblastosis but not for gp55-mediated erythroid proliferation. Interestingly, the murine EPOR, which is required for gp55-mediated Ba/F3-cell proliferation, was dispensable for erythroblastosis in vivo. Finally, gp55-mediated activation of the EPOR and STAT5 are required for Friend virus-induced polycythemia. These results suggest that Friend virus activates both sf-STK and the EPOR to cause deregulated erythroid proliferation and differentiation.
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PMID:Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia. 1617 61

Extract: Tyrosine kinases are a large and diverse family of proteins found only in Metazoans. The ERBB receptor tyrosine kinases (RTK), the main focus of this article, belong to the sub-group encompassing the cell surface proteins. All receptor tyrosine kinases have an extracellular domain that binds peptide ligands, span the membrane once, and have an intracellular portion with protein tyrosine kinase activity. Ligand binding to receptor tyrosine kinases induces the formation of receptor dimers and activates the kinase domain of the receptor, which transfers a phosphate group from the bound ATP to specific tyrosine side chains on the receptor proteins and on intracellular signaling proteins that bind the active receptor tyrosine kinases. In many types of human tumors, ERBB (erythroblastosis group B) receptor tyrosine kinases are aberrantly activated and contribute to cancer development. Accordingly, these receptors have been intensely studied both to understand their roles in cancer biology and to employ them as therapeutic targets. Many ERBB targeted inhibitors are now in clinical use.
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PMID:Receptor tyrosine kinases as therapeutic targets in cancer. 2070 47


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