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)

A deficiency of the enzyme arylsulfatase B results in the lysosomal storage disorder Maroteaux-Lamy syndrome or mucopolysaccharidosis type VI. Severe, intermediate and mild forms of this autosomal recessively inherited disease can be clinically differentiated. To determine the molecular defect in a patient with the intermediate form of the disorder, DNA fragments generated from the patient's mRNA by reverse transcription and subsequent amplification by the polymerase chain reaction were subcloned and sequenced. The mRNA transcribed from one allele contains a 244-base pair deletion causing a frameshift and a truncation of the open reading frame. The C-terminal third of the encoded mutant polypeptide has a nonsense sequence. This mutation is due to a deletion of exon 5 in this allele. A silent A to G transition at nucleotide 1191 was present in the same allele, and the second allele was characterized by a T to C transition at nucleotide 1600 causing a mutation of the translational stop codon to a glutamine codon (*534Q) and extending the encoded polypeptide by 50 amino acids. Stable expression of the *534Q allele in LTK- cells resulted in a mutant precursor 4 kDa larger than the wild-type precursor. The majority of the mutant precursor appears to be degraded before reaching the trans Golgi. This is consistent with an altered polypeptide structure, where a number of missing or masked epitopes were observed in an enzyme immunobinding assay using a panel of monoclonal antibodies. Immunoquantification analysis showed that epitopes were most likely masked, as missing epitopes could be reformed by binding the mutant protein to a polyclonal antibody of arylsulfatase B. It is suggested that the additional amino acids at the C terminus of the arylsulfatase B polypeptide induce a protein conformational change. *534Q mutant polypeptide escaping degradation is sorted to dense lysosomes. The mutant polypeptide has an approximately 9-fold higher catalytic efficiency than wild-type arylsulfatase B.
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PMID:Juvenile form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). A C-terminal extension causes instability but increases catalytic efficiency of arylsulfatase B. 814 52

Epidermal Growth Factor in a polypeptide growth factor of which receptor EGFR has a prognosis value for some malignant tumours. Data are limited concerning the EGFR value in cervix tumours. EGFR was measured in biopsies obtained in cervix cancer patients before any treatment. Twenty-two patients (18 squamous carcinomas, 4 adenocarcinomas) were studied. EGF binding was characterized in seven tumour samples. Scatchard representation identified a single family of binding sites. Kd value revealed high affinity for EGF binding: 0.645 +/- 0.769 nmol/l. EGFR values were determined by a simplified competition method using a radiolabeled ligand. EGFR was found to be more elevated in tumours (n = 20) than in normal tissue (n = 4): (59.5 vs 10.5 fmol/mg proteins). There was a tendency for higher EGFR values in squamous tumours (m = 83.5 fmol/mg proteins) as compared to adenocarcinomas (m = 35.5 fmol/mg proteins), P = 0.09. There was no difference in the distribution of EGFR values according to tumour differentiation and staging. This work confirms the presence of EGFR in cervix tumours. Interestingly, we found that tumours with high EGFR values were more radiosensitive than tumours with low values.
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PMID:[Demonstration and characterization of EGF receptors in cancer of the uterine cervix]. 817 74

Platelet-derived growth factor (PDGF) is a disulfide-linked dimer comprised of two related polypeptide chains. To investigate the effects of an inactivating lesion introduced into one chain of the nascent PDGF dimer, approaches were developed to optimize synthesis, assembly, secretion, and purification of heterodimers between normal PDGF A and wild-type or mutant PDGF B. PDGF AB heterodimers were released into culture fluids less efficiently than PDGF AA, but to a greater degree than the cell-associated PDGF BB. These results suggest that interactions between two chains influence PDGF secretion. Analysis of heterodimers between PDGF A and disabled PDGF B mutants on cells that express either alpha or beta PDGFRs demonstrated that the impaired biologic activity of the mutant PDGF B chain was ameliorated with respect to binding and triggering of alpha PDGFRs. In cells that expressed both receptor types, heterodimers of mutant PDGF B and wild-type PDGF A gained substantially in their ability to recruit and trigger alpha, but not beta, PDGFRs. Partial rescue of impaired PDGF B mutant chain function by dimer formation with a wild-type PDGF A chain implies that interchain interactions markedly affect PDGFR binding and activation.
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PMID:Platelet-derived growth factor AB heterodimer interchain interactions influence secretion as well as receptor binding and activation. 821 43

Tetrahymena thermophila micronuclei contain four linker-associated proteins, alpha, beta, gamma, and delta. Synthetic oligonucleotides based on N-terminal protein sequences of beta and gamma were used to clone the micronuclear linker histone (MLH) gene. The MLH gene is single copy and is transcribed into a 2.4-kb message encoding all four linker-associated proteins. The message is translated into a polypeptide (Mic LH) that is processed at the sequence decreases RTK to give proteins whose amino acid sequences differ markedly from each other, from the sequence of macronuclear H1, and from sequences of typical H1s of other organisms. This represents the first example of multiple chromatin proteins derived from a single polyprotein. The delta protein consists largely of two high-mobility-group (HMG) boxes. An evolutionary analysis of HMG boxes indicates that the delta HMG boxes are similar to the HMG boxes of tsHMG, a protein that appears in elongating mouse spermatids when they condense and cease transcription, suggesting that delta could play a similar role in the micronucleus. The micronucleus divides mitotically, while the macronucleus divides amitotically. Surprisingly, macronuclear H1 but not Mic LH contains sequences resembling p34cdc2 kinase phosphorylation sites, while each of the Mic LH-derived proteins contains a typical protein kinase A phosphorylation site in its carboxy terminus.
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PMID:Four distinct and unusual linker proteins in a mitotically dividing nucleus are derived from a 71-kilodalton polyprotein, lack p34cdc2 sites, and contain protein kinase A sites. 826 78

Hepatocyte growth factor/scatter factor (HGF/SF) is secreted by cells of mesodermal origin and shows powerful mitogenic, motogenic and morphogenic activities on epithelial and endothelial cells. It is a heparin-binding polypeptide with an alpha/beta heterodimeric structure, showing structural homologies with enzymes of the blood clotting cascade. HGF binds with high affinity to the receptor encoded by the MET protooncogene (p190MET). The MET receptor is a heterodimer of two disulfide-linked subunits (alpha and beta); the alpha subunit is extracellular, while the beta is transmembrane and endowed with tyrosine kinase activity. The HGF-triggered signalling is mediated by different cytoplasmic effectors, including phosphatidylinositol 3-kinase, phospholipase C-gamma, and Src-related tyrosine kinases. p190MET is expressed in several normal epithelial tissues (e.g., liver, gastrointestinal tract, kidney) and is often overexpressed in neoplastic cells. p190MET expression has been reported also in central nervous system microglia, a monocyte-derived cell population. We recently found that p190MET is expressed in selected peripheral blood cell populations, such as macrophages. The amount of both mRNA and protein is barely detectable, while it is dramatically increased upon activation. These findings suggest that HGF may play a role in hemopoietic cell signaling, during activation and differentiation of blood cell lineages.
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PMID:The hepatocyte growth factor and its receptor. 840 Dec 59

The stress-responsive DDR2 gene (previously called DDRA2) of Saccharomyces cerevisiae is transcribed at elevated levels following stress caused by heat shock or DNA damage. Previously, we identified a 51-bp promoter fragment, oligo31/32, which conferred heat shock inducibility on the heterologous CYC1-lacZ reporter gene in S. cerevisiae (N. Kobayashi and K. McEntee, Proc. Natl. Acad. Sci. USA 87:6550-6554, 1990). Using a series of synthetic oligonucleotides, we have identified a pentanucleotide, CCCCT (C4T), as an essential component of this stress response sequence. This element is not a binding site for the well-characterized heat shock transcription factor which recognizes a distinct cis-acting heat shock element in the promoters of many heat shock genes. Here we demonstrate the ability of oligonucleotides containing the C4T sequence to confer heat shock inducibility on the reporter gene and show that the presence of two such elements produces more than additive effects on induction. Gel retardation experiments have been used to demonstrate specific complex formation between C4T-containing fragments and one or more yeast proteins. Formation of these complexes was not competed by fragments containing mutations in the C4T sequence nor by heat shock element-containing competitor DNAs. Fragments containing the C4T element bound to a single 140-kDa polypeptide, distinct from heat shock transcription factors in yeast crude extracts. These experiments identify key cis- and trans-acting components of a novel heat shock stress response pathway in S. cerevisiae.
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PMID:Identification of cis and trans components of a novel heat shock stress regulatory pathway in Saccharomyces cerevisiae. 841 30

Motor neurons stimulate their postsynaptic muscle targets to synthesize neurotransmitter receptors. Polypeptide signaling molecules may mediate this inductive interaction. Here we report the purification of ARIA, a protein that stimulates the synthesis of muscle acetylcholine receptors, and the isolation of ARIA cDNA. Recombinant ARIA increases acetylcholine receptor synthesis greater than 3-fold, and it induces tyrosine phosphorylation of a 185 kd muscle protein. The ARIA cDNA hybridizes with mRNAs that are expressed in the spinal cord from E4, a time prior to the onset of neuromuscular synapse formation, through adulthood. By E7, hybridizing mRNAs are concentrated in motor neurons. Chicken ARIA is homologous to the rat Neu differentiation factor and human here-gulin, ligands for the receptor tyrosine kinase encoded by the neu (c-erbB2, HER2) proto-oncogene. Our data suggest that members of the ARIA protein family promote the formation and maintenance of chemical synapses and, furthermore, that receptor tyrosine kinases play important roles in this process.
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PMID:ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. 845 70

Three cDNA fragments that encoded all but the extreme N terminus of the rat ErbB3 protein were cloned by low-stringency screening of a rat liver cDNA library with a human ERBB3 probe. The remaining 5'-end of the cDNA was generated by a reverse transcription-polymerase chain reaction method, and a single full-length rat ErbB3 cDNA was assembled. A comparison of the deduced amino acid (aa) sequences of human and rat ErbB3 was made, and the effects of certain aa substitutions in the putative protein tyrosine kinase domain were considered. The rat ErbB3 cDNA was subsequently expressed in cultured NIH-3T3 mouse fibroblasts, in which a high level of approx. 180-kDa recombinant ErbB3 (re-ErbB3) was generated. The rat re-ErbB3 produced in transfected fibroblasts was responsive to the polypeptide, heregulin, a known ligand for ErbB3. Challenge of transfected fibroblasts with heregulin stimulated the phosphorylation of rat re-ErbB3 on Tyr residues and promoted its association with the p85 subunit of phosphatidylinositol 3-kinase. Together, these results indicate that a fully functional rat ErbB3 cDNA has been isolated, and that fibroblast cells expressing this cDNA will be suitable for investigations of the signal transduction mechanism of ErbB3.
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PMID:Cloning of the rat ErbB3 cDNA and characterization of the recombinant protein. 852 90

Recombinant human neu differentiation factor produced in engineered E. coli was isolated and subject to structural characterization. The recombinant molecule can be prepared to apparent purity and is active in stimulating receptor tyrosine autophosphorylation in cultural cells expressing HER2 receptor. The 229 amino-acid polypeptide consists of eight cysteines, of which two cysteines near the N-terminus are disulfide-bonded to form an immunoglobulin-like domain and the remaining six cysteines at the C-terminus cross-link to form an epidermal growth factor-like structure. Detailed chemical characterization of the recombinant molecule by peptide mapping in conjunction with Edman sequencing and mass spectrometry reveals that the bacterially produced recombinant neu differentiation factor preparation is properly folded and contains the correct disulfide structure. The peptide mapping procedure is also useful in identifying abnormal peptides derived from deamidation and oxidation of Asn and Met residues, respectively.
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PMID:Isolation and structural characterization of recombinant human neu differentiation factor expressed in Escherichia coli. 854 41

Long-chain acyl-CoA hydrolase (EC 3.1.2.2), which is found primarily in the brain in rats, catalyzes the hydrolysis of fatty acyl-CoA thioesters. We purified this enzyme, referred to as ACH, from the rat brain cytosol. The molecular masses of the native enzyme and the subunit were estimated to be 104 and 36 kDa, respectively. The enzyme showed high activity with long-chain acyl-CoAs, e.g., with maximal velocity of 262 mumol/min/mg and Km of 5.7 microM for palmitoyl-CoA, but acyl-CoAs with carbon chain lengths of C8-18 were also good substrates. The enzyme was refractory to the inhibitory effect of diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride, but sensitive to p-chloromercuribenzoate. In the rat brain cytosol, about 90% of palmitoyl-CoA hydrolase activity was titrated by anti-ACH antibody, which accounted for over 70% of the enzyme activity found in the brain tissue. Immunoblots of the cytosol prepared from rat brain regional blocks indicated the broad distribution of ACH over the brain, with a relatively high level in the pons and medulla. Immunohistochemically, ACH was localized to neurons. In addition to various nuclei, some neuronal cells, such as mitral cells in the olfactory bulb, pyramidal cells in the cerebral cortex, and Purkinje cells in the cerebellum, were also immunostained with anti-ACH antibody. Brain cytosols prepared from ten mammalian species including human contained a single polypeptide reactive to anti-ACH antibody with molecular masses of 34-36 kDa, together with high activities of palmitoyl-CoA hydrolase. These findings suggest the physiological significance of ACH in the brain, although its precise role remains to be determined.
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PMID:Long-chain acyl-CoA hydrolase from rat brain cytosol: purification, characterization, and immunohistochemical localization. 857 57


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