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 recent identification of an activator for the ErbB2/Neu receptor has uncovered a new family of polypeptide growth factors that undoubtedly play a major role in the regulation of neuronal growth and differentiation. These factors, called the neuregulins, are expressed in neural and mesenchymal tissues, and activate members of the epidermal growth factor family of receptor tyrosine kinases. The identification and characterization of the neuregulins and their receptors will facilitate the dissection of the biochemical pathways regulating nervous system development.
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PMID:Neuregulins and their receptors. 858 Jul 12

Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
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PMID:Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties. 858 55

Single-chain Fv (sFv) molecules consist of the two variable domains of an antibody (Ab) connected by a polypeptide spacer and contain the binding activities of their parental antibodies (Abs). In this paper we have attached the C-terminus of 2C11-sFv (anti-mouse CD3 epsilon-chain) to the N-terminus of OKT9-sFv (anti-human transferrin receptor [TfR]) through a 23 amino acid inter-sFv linker consisting primarily of CH1 region residues from 2C11, to form a single-chain bispecific Fv2 [bs(sFv)2] molecule. The bs(sFv)2 was expressed in COS-7 cells, and was secreted at the same rate as the two parental sFvs. The secreted protein had both anti-CD3 and anti-TfR binding activities. Essentially all of the secreted bs(sFv)2 molecules bound TfR and the binding affinity of the bs(sFv)2 was comparable to that of OKT9 sFv and Fab. Thus, the attachment of the inter-sFv linker to the N-terminus of OKT9-sFv did not impair its binding function. The bs(sFv)2 retained both binding specificities after long-term storage at 4 degrees C or overnight incubation at 37 degrees C. It redirected activated mouse CTL to specifically lyse human TfR+ target cells at low (ng/ml) concentrations and was much more active than a chemically cross-linked heteroconjugate prepared from the same parental mAbs. Because bs(sFv)2 molecules secreted by mammalian cells are homogeneous proteins containing two binding sites in a single polypeptide chain, they hold great promise as an easily obtainable, economic source of a bispecific molecule suitable for in vivo use.
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PMID:A single-chain bispecific Fv2 molecule produced in mammalian cells redirects lysis by activated CTL. 864 42

A 220-bp fragment of PTK7 cDNA was previously cloned from normal human melanocyte RNAs by means of the reverse transcription-polymerase chain reaction [Lee, S.-T., Strunk, K.M., and Spritz, R.A. (1993) Oncogene 8, 3403-3410]. We now report the cloning of the human full-length PTK7 cDNA and its characterization. The 1,070 amino acid PTK7 polypeptide deduced from the cDNA sequence constitutes receptor protein tyrosine kinase (RPTK), but has several unusual residues in some of the highly conserved tyrosine kinase motifs. PTK7 mRNA was expressed at the highest level in a human erythroleukemia cell line among tested samples, and at relatively high levels in liver, lung, pancreas, kidney, placenta, and melanocytes. Human PTK7 is 72% identical to chick KLG, suggesting that PTK7 is homologous or possibly orthologous to chick KLG, and that these represent a new subfamily of RPTKs.
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PMID:Characterization of the human full-length PTK7 cDNA encoding a receptor protein tyrosine kinase-like molecule closely related to chick KLG. 888 11

The DDR2 gene is a multistress response gene in Saccharomyces cerevisiae that is transcriptionally activated by more than thirteen xenobiotic agents and environmental or physiological stresses. The DDR2 gene encodes a small hydrophobic 61 amino acid polypeptide located on chromosome XV adjacent to the SPE2 locus. Disruption alleles of the DDR2 gene have been constructed and these ddr2 delta mutants show no defect in heat shock recovery or thermotolerance and appear normal for DNA damage sensitivity and mutagenesis.
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PMID:Structure and functional analysis of the multistress response gene DDR2 from Saccharomyces cerevisiae. 895 34

Detergent-permeabilized EGFR-T17 fibroblasts, which overexpress the human epidermal growth factor (EGF) receptor, phosphorylate both poly-L-(glutamic acid, tyrosine) and exogenous calmodulin in an EGF-stimulated manner. Phosphorylation of calmodulin requires the presence of cationic polypeptides, such as poly-L-(lysine) or histones, which exert a biphasic effect toward calmodulin phosphorylation. Optimum cationic polypeptide/calmodulin molar ratios of 0.3 and 7 were determined for poly-L-(lysine) and histones, respectively. Maximum levels of calmodulin phosphorylation were attained in the absence of free calcium, and a strong inhibition of this process was observed at very low concentrations (Ki = 0.2 microM) of this cation. The incorporation of phosphate into calmodulin occurred predominantly on tyrosine residue(s) and was stimulated 34-fold by EGF.
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PMID:Phosphorylation of calmodulin by permeabilized fibroblasts overexpressing the human epidermal growth factor receptor. 904 62

In a search for novel tyrosine kinases involved in vertebrate development, we have isolated cDNAs corresponding to three distinct members of the Eph-family of receptor tyrosine kinases. Whole mount RNA in situ hybridization analysis showed all three genes were most abundantly expressed in the developing nervous system. zek1 (zebrafish Eph-like kinase1) encodes a 981 amino acid polypeptide closely related to the murine Sek1 and Bsk receptors. Cos-1 cells transfected with zek1 produce a 141 kilodalton tyrosine phosphorylated protein which is recognized by antibodies raised against two predicted Zek1 peptides. These antibodies also recognized a protein of the same apparent molecular weight in lysates from zebrafish embryos and adults. Widespread expression of zek1 in the developing brain and neural tube suggested a generalized function of the Zek1 receptor in neuronal cell ontogeny.
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PMID:Novel Eph-family receptor tyrosine kinase is widely expressed in the developing zebrafish nervous system. 918 52

AML1 is involved at the breakpoint of chromosome 21 band q22 in several recurring chromosomal translocations associated with myeloid and lymphoid leukemias. AML1 corresponds to CBFA2, and encodes one of the DNA-binding subunits of the enhancer core binding factor CBF. Other members of this family of DNA-binding proteins are CBFA1 and CBFA3, also known as AML3 and AML2. The three proteins are characterized by a highly conserved domain (runt domain, > 90% homology) at the amino end that is necessary for DNA-binding and protein dimerization, and by a unique domain at the carboxyl end that is necessary for transactivation. Two recurring chromosomal translocations involving AML1 associated with myeloid leukemias are the t(8;21)(q22;q22), seen in 20% of patients with acute myeloid leukemia (AML) M2, and the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. In five patients with a t(3;21) whom we studied, AML1 is interrupted by the translocation breakpoint between the runt domain and the transactivation domain, and is fused to two genes on chromosome band 3q26: EAP, which encodes the ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of the five patients we studied, a fusion with a third gene EVI1 also occurs. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric junction AML1/MDS1/EVII has been detected in cells from one of our patients with the 3;21 translocation. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. We have compared the normal AML1 to AML1/MDS1 and AML1/EAP as transcriptional regulators of the CSF1R promoter which contains the CBF target sequence. Our results indicate that whereas the normal AML1 can activate the promoter, the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. To determine the role of the chimeric proteins in cell growth, we expressed their cDNA in rat fibroblasts. When either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. However, only cells expressing AML1/MDS1 grow as large tumors in nude mice. Thus, although both chimeric genes have similar effects in transactivation of the CSF1R promoter, they affect cell growth as tumor promoters differently in vivo.
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PMID:Rearrangements of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: in vitro and in vivo studies. 920 63

Flt4 is a receptor protein tyrosine kinase that is expressed in the adult lymphatic endothelium and high endothelial venules. We have used a BIAcore assay to identify rodent and human cell conditioned media containing the ligand of Flt4 (Flt4-L). Receptor-based affinity chromatography was used to purify this growth factor, followed by amino acid sequencing and molecular cloning of the murine cDNA, the orthologue of human vascular endothelial growth factor-C and vascular endothelial growth factor related protein. The murine flt4-L gene was localized to chromosome 8 and demonstrated to be widely expressed. Flt4-L was found to have a hydrophobic signal sequence and a pro-peptide-like sequence that is removed to generate the mature N-terminus. In addition, the C-terminal region of Flt4-L has four repeats of a cysteine-rich motif that is presumably also proteolytically processed to generate the 21000 Mr polypeptide subunit of the Flt4-L homodimer. Recombinant Flt4-L activated Flt4 as judged by induction of tyrosyl phosphorylation, and induced mitogenesis in vitro of lymphatic endothelial cells.
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PMID:Characterization of murine Flt4 ligand/VEGF-C. 924 16

VEGF-C is a recently discovered secreted polypeptide related to the angiogenic mitogen VEGF. We have isolated the quail VEGF-C cDNA and shown that its protein product is secreted from transfected cells and interacts with the avian VEGFR3 and VEGFR2. In situ hybridization shows that quail VEGF-C mRNA is strongly expressed in regions destined to be rich in lymphatic vessels, particularly the mesenteries, mesocardium and myotome, in the region surrounding the jugular veins, and in the kidney. These expression sites are similar to those observed in the mouse embryo (E. Kukk, A. Lymboussaki, S. Taira, A. Kaipainen, M. Jeltsch, V. Joukov and K. Alitalo, 1996, Development 122, 3829-3837). We have observed VEGFR3-positive endothelial cells in proximity to most of the VEGF-C-expressing sites, suggesting functional relationships between this receptor-ligand couple. The comparison of the VEGF and VEGFR2 knockout phenotypes had suggested the existence of another ligand for VEGFR2. We therefore investigated the effect of VEGF-C on VEGFR2-positive cells isolated from the posterior mesoderm of gastrulating embryos. We have recently shown that VEGF binding triggers endothelial differentiation of these cells, whereas hemopoietic differentiation appears to be mediated by binding of a so far unidentified VEGFR2 ligand. We show here that VEGF-C also triggers endothelial differentiation of these cells, presumably via VEGFR2. These results indicate that VEGF and VEGF-C can act in a redundant manner via VEGFR2. In conclusion, VEGF-C appears to act during two different developmental phases, one early in posterior mesodermal VEGFR2-positive endothelial cell precursors which are negative for VEGFR3 and one later in regions rich in lymphatic vessels at a time when endothelial cells express both VEGFR2 and VEGFR3.
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PMID:Avian VEGF-C: cloning, embryonic expression pattern and stimulation of the differentiation of VEGFR2-expressing endothelial cell precursors. 943 94


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