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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Varicella-zoster virus (VZV) glycoprotein gpI, the homolog of herpes simplex virus gE, functions as a receptor for the Fc portion of immunoglobulin G. Like other cell surface receptors, this viral receptor is highly phosphorylated in cell culture. To identify the precise location of the cellular kinase-mediated phosphorylation, we generated a tailless deletion mutant and several point mutants which had altered serine and threonine residues within the cytoplasmic domain of gpI. The mutated and wild-type genes of gpI were transfected and expressed within a vaccinia virus-T7 polymerase transfection system in order to determine what effect these mutations had on the phosphorylation state of the protein in vivo and in vitro. Truncation of the cytoplasmic domain of gpI diminished the phosphorylation of gpI in vivo. Examination of the point mutants established that the major phosphorylation sequence of gpI was located between amino acids 593 and 598, a site which included four phosphorylatable serine and threonine residues. Phosphorylation analyses of the mutant and wild-type glycoproteins confirmed that gpI was a substrate for casein kinase II, with threonines 596 and 598 being critical residues. Although the mutant glycoproteins were phosphorylated by casein kinase I, protease V8 partial digestion profiles suggested that casein kinase II exerted the major effect. Thus, these mutagenesis studies demonstrated that the gpI cytoplasmic sequence Ser-Glu-Ser-Thr-Asp-Thr was phosphorylated in mammalian cells in the absence of any other herpesvirus products. Since the region defined by transfection was consistent with results obtained with in vitro phosphorylation by casein kinase II, we propose that VZV gpI is a physiologic substrate for casein kinase II. Immunofluorescence and pulse-chase experiments demonstrated that the mutant glycoproteins were processed and transported to the outer cell membrane.
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PMID:Identification of the phosphorylation sequence in the cytoplasmic tail of the varicella-zoster virus Fc receptor glycoprotein gpI. 839 91

We reported previously that the posttranslational processing associated with phosphorylation of the herpes simplex virus 1 infected-cell protein 22 (ICP22), a regulatory protein, is encoded by UL13, a gene encoding a structural protein of the virion. We now report the following. (i) In cells infected with a mutant lacking UL13 (delta UL13), restricted infected cells accumulate reduced levels of the regulatory protein ICP0 and several late viral proteins. Identical reductions have been observed in the same cell lines infected with a mutant from which the alpha 22 gene, encoding ICP22, had been deleted (delta alpha 22). We conclude that the UL13-mediated processing of ICP22 is essential for its gene-regulatory function. (ii) The reduced accumulations of specific viral protein in cells infected with either delta UL13 or delta alpha 22 viruses correlate with reduced levels of specific mRNAs for both ICP0 and the affected late genes. (iii) ICP22 is not modified by the UL13 protein introduced into cells during infection. (iv) ICP22 is also modified by the protein kinase encoded by US3, but this modification is different from that of the UL13 protein kinase. These results predict that UL13 encodes a protein kinase or phosphotransferase which is expressed late in the replicative life cycle and which directly or indirectly phosphorylates ICP22. This modification is essential for stabilization or increased transcription of a specific subset of viral RNAs and, ultimately, for the accumulation of corresponding viral proteins.
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PMID:Processing of the herpes simplex virus regulatory protein alpha 22 mediated by the UL13 protein kinase determines the accumulation of a subset of alpha and gamma mRNAs and proteins in infected cells. 839 74

The DNA sequence of the whole of the short unique region (U(s)) and that of part of the short terminal repeat (TRs) of herpesvirus of turkeys (HVT) were determined. HVT U(s) is 8.6 kbp long and contains eight potential open reading frames (ORFs). Seven of these have counterparts in the U(s) of herpes simplex virus type 1 (HSV-1). The homologous proteins include US1, US2, US10, protein kinase (US3) and the glycoproteins gD, gI and gE. In addition, HVT contains one ORF which has a counterpart in the U(s) of Marek's disease virus (MDV) but is not homologous to any other known herpesvirus gene. Although HVT and MDV proteins encoded by U(s) genes have evident similarities with proteins encoded by alphaherpesviruses, multiple alignment analysis of predicted amino acid sequences show that HVT proteins are more closely related to MDV proteins than to homologous proteins of mammalian alphaherpesviruses. The percentage amino acid identity between HVT and MDV U(s)-encoded proteins ranges from 35 to 65, the most conserved protein being encoded by the homologues of the HSV-1 US2 gene. Most of the genes are colinear with those of HSV-1 except US10 which is transposed in HVT and MDV. A characteristic feature of HVT is the fact that approximately two-thirds of the gE gene is located in the inverted repeats flanking U(s).
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PMID:The complete sequence and gene organization of the short unique region of herpesvirus of turkeys. 840 40

The herpes simplex virus type 1 genome encodes a set of genes (alpha genes) expressed in the absence of de novo viral protein synthesis. Earlier studies have shown that the product of the alpha 22 gene, a member of this set, is nucleotidylylated by casein kinase II and phosphorylated by viral protein kinases encoded by UL13 and US3. Mutants lacking the carboxyl-terminal domain starting with amino acid 200 exhibit reduced capacity to replicate in primary human cell strains or in cells of rodent derivation and also exhibit reduced expression of a subset of gamma or late genes. We report that the domain of the alpha 22 gene is transcribed by two 3'-coterminal mRNAs. The longer transcript reported encodes the 420-amino-acid alpha 22 protein, whereas the shorter transcript reported here encodes a protein containing the carboxyl-terminal 273 amino acids of the alpha 22 protein. The shorter gene is designated US1.5. The US1.5 mRNA is synthesized in cells infected and maintained in the presence of cycloheximide and under other conditions which restrict viral gene expression to alpha genes. In-frame insertion of linkers encoding 18, 21, or 22 amino acids after codon 200 or 240 of the alpha 22 protein did not affect the known functions or phenotype associated with the wild-type alpha 22 gene or its product. Earlier studies have placed the nucleotidylylated sequences in the amino-terminal portion of the protein. The results of these studies indicate that the US1.5 gene encodes the functions associated with replication in human primary or rodent cells and optimal expression of alpha 0 and gamma genes. This finding brings the number of genes known to map in the unique short region of the herpes simplex virus type 1 DNA to 14 and the total number of different genes to 78.
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PMID:The promoter and transcriptional unit of a novel herpes simplex virus 1 alpha gene are contained in, and encode a protein in frame with, the open reading frame of the alpha 22 gene. 852 23

Efficient expression of herpes simplex virus genes requires the synthesis of functional ICP4, a nuclear phosphoprotein that contains a prominent serine-rich region between amino acids 142 and 210. Residues in this region not only are potential sites for phosphorylation but also are involved in the functions of ICP4. By comparing the growth of a virus in which this region is deleted (d8-10) with wild-type virus (KOS) in PC12 cells or PC12 cells that are deficient in cyclic AMP-dependent protein kinase (PKA), two observations were made: (i) the growth of wild-type virus was impaired by 1 to 2 orders of magnitude in the PKA-deficient cells, indicating the involvement of PKA in the growth cycle of herpes simplex virus type 1, and (ii) while the growth of d8-10 was impaired by almost 2 orders of magnitude in wild-type cells, it was not further impaired (as was that of wild-type virus) in PKA-deficient cells, implicating the region deleted in d8-10 as a possible target for cellular PKA. In trigeminal'ganglia of mice, the d8-10 mutant virus grew poorly; however, it established latency in nearly 90% of ganglia tested. Studies of the phosphorylation of wild-type and d8-10 ICP4 proteins revealed that the serine-rich region is a major determinant for phosphorylation of ICP4 in vivo and that the phosphorylation state could change as a function of the PKA activity. Consistent with this observation, the serine-rich region of ICP4 was shown to be a target for PKA in vitro. While intact ICP4 was readily phosphorylated by ICP4 in vitro, the d8-10 mutant ICP4 was not. Moreover, a synthethic peptide representing a sequence in the serine tract that is predicted to be a substrate for PKA was phosphorylated by PKA in vitro, having a Km within the physiological range. These data suggest that PKA plays a role in viral growth through phosphorylation of one or more sites on the ICP4 molecule.
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PMID:Role of protein kinase A and the serine-rich region of herpes simplex virus type 1 ICP4 in viral replication. 855 63

The herpes simplex virus ICP4 protein is required for induction of early and late viral gene transcription as well as for repression of expression of its own gene and several other viral genes. Several electrophoretic forms of ICP4 have been observed, and phosphorylation is thought to contribute to this heterogeneity and possibly to the multiple functions of ICP4. To define the complexity of the site(s) of phosphorylation of ICP4 and to initiate mapping of this site(s), we have performed two-dimensional phosphopeptide mapping of wild-type and mutant forms of ICP4 labeled in infected cells or in vitro. Wild-type ICP4 labeled in infected cells shows a complex pattern of phosphopeptides, and smaller mutant forms of ICP4 show progressively fewer phosphopeptides, arguing that multiple sites on ICP4 are phosphorylated. The serine-rich region of ICP4, residues 175 to 198, was shown to be a site for phosphorylation. Furthermore, the serine-rich region itself or the phosphorylation of this region increases phosphorylation of all phosphopeptides. A mutant ICP4 molecule lacking the serine-rich region showed low levels of phosphorylation by protein kinase A or protein kinase C in vitro. These results suggest that there may be a sequential phosphorylation of ICP4, with phosphorylation of the serine-rich region stimulating phosphorylation of the rest of the molecule. In addition, purified ICP4 showed an associated kinase activity or an autophosphorylation activity with properties different from those of protein kinase A or protein kinase C.
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PMID:Analysis of phosphorylation sites of herpes simplex virus type 1 ICP4. 855 64

The gene coding for the large subunit of herpes simplex virus type 2 ribonucleotide reductase (RR) (ICP10) has a unique 5' terminal domain the product of which has a serine/threonine (Ser/Thr) protein kinase (PK) catalytic domain preceded by a transmembrane (TM) segment. Because ICP10 localizes on the cell surface and is internalized by the endocytic pathway like an activated growth factor receptor (Hunter et al., 1995, Virology 210, 345-360), we asked whether it is ligand-inducible in order to examine whether it has intrinsic transphosphorylating activity. We constructed a chimeric expression vector that contains the extracellular and TM domains of the epidermal growth factor receptor (EGFR) joined to the intracellular PK and RR domains of ICP10 (pCH5) and established constitutively expressing cell lines in NIH3T3 2.2 cells that do not express EGFR. The chimeric protein, designated p210 CH5, localized to the surface of these cells as determined by immunofluorescent staining with MAb EGFR, and it bound 125I-EGF.p210 CH5 coprecipitated with protein species p170, p120, p88, p60, p44, p34, and p25. EGF treatment activated the PK activity of p210 CH5, resulting in its autophosphorylation and the phosphorylation of the p120, p88, and p34 species. Immunoprecipitation/immunoblotting with anti-ras-GAP antibody and phosphoamino acid analysis indicated that p120 is ras-GAP and it is phosphorylated on Ser/Thr residues. The identities of the phosphorylated p88 and p34 are still unknown. The data indicate that when fused to a ligand-regulated extracellular domain (EGFR), the ICP10 PK auto- and transphosphorylating activities are ligand-inducible. These findings support the interpretation that the ICP10 PK activity is intrinsic and indicate that ras-GAP is one of its phosphorylation substrates.
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PMID:The protein kinase activity of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) fused to the extracellular domain of the epidermal growth factor receptor is ligand-inducible. 861 Apr 33

The large subunit of herpes simplex virus (HSV) ribonucleotide reductase (RR1) designated ICP6 and ICP10 for HSV-1 and HSV-2, respectively, has a novel protein kinase (PK) enzymatic activity. ICP10 is localized on the cell surface, a localization that depends on an intact transmembrane (TM) segment. We used immunocomplex PK assays to examine the PK activity of ICP10 in stably transfected eukaryotic cells. Activity was distinct from that of casein kinase II (CKII) in that it did not require monovalent ions and was not inhibited by zinc sulfate. PK activity was eliminated by deletion of the conserved PK catalytic motifs or of the TM segment and it was significantly impaired by mutation of the invariant Lys (Lys176). Loss of PK activity by Lys176 mutation resulted in the failure to bind ATP. A truncated ICP10 PK expressed in bacteria (pp29 1a1) retained auto- and transphosphorylating activity (for calmodulin) after purification to apparent homogeneity. PK activity was also absent in cells infected with a recombinant virus (ICP10 delta PK) deleted in the ICP10 PK catalytic motifs. In cells infected with HSV-1 or HSV-2, RR1 had auto- and transphosphorylating activity for the small subunit of HSV ribonucleotide reductase (RR2) and immunoglobulin G (IgG). Comparing the PK activity of ICP6 and ICP10 we found that ICP6 requires five-fold higher concentrations of [gamma-32P]ATP than ICP10 and both enzymes are Mn2+ dependent, which is also different from CKII that is primarily Mg2+-dependent. Similar results were obtained for various HSV strains and in different cell lines. The data are consistent with the conclusion that the RR1 PK activity is intrinsic.
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PMID:The novel protein kinase of the RR1 subunit of herpes simplex virus has autophosphorylation and transphosphorylation activity that differs in its ATP requirements for HSV-1 and HSV-2. 861 85

The transcription factors Oct-1 and Oct-2 bind differentially to three octamer binding sequences corresponding to the octamer binding site from the H2B promoter [ATGCTAATAA], a simple TAATGARAT motif, found in herpes simplex virus IE4/5 genes [GCGGTAATGAGAT], and a perfect consensus overlapping octamer/TAATGARAT motif [ATGCTAATGAGAT]. By comparing the effects of protein kinase A, protein kinase C and casein kinase 2 in vitro on the binding of Oct-1 and Oct-2 to the three motifs, we show that the actions of these kinases regulate Oct-1 and Oct-2 DNA binding independently of each other in a binding-site-specific manner. Inhibition of cellular phosphatases also regulate Oct-1 and Oct-2 DNA binding in a binding-site-specific manner. Both kinase and phosphatase activity are important for regulating the DNA binding activity of Oct-1 and Oct-2 because, in the presence of phosphatase inhibitors, protein kinase A attenuates the binding of both Oct-1 and Oct-2 to the octamer binding site but enhances binding when phosphatase inhibitors are omitted. Thus the DNA specificity of Oct-1 and Oct-2 can be regulated in vitro by the action of different kinases.
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PMID:Oct-1 [corrected] and Oct-2 DNA-binding site specificity is regulated in vitro by different kinases. 864 73

The large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) is a multifunctional protein. It consists of a ribonucleotide reductase and a serine/threonine protein kinase (PK) domain, which has three proline-rich motifs consistent with SH3-binding sites at positions 140, 149, and 396. We used site-directed mutagenesis to identify amino acids required for kinase activity and interaction with signaling proteins. Mutation of Lys176 or Lys259 reduced PK activity (5-8-fold) and binding of the 14C-labeled ATP analog rho-fluorosulfonylbenzoyl 5'-adenosine (FSBA) but did not abrogate them. Enzymatic activity and FSBA binding were abrogated by mutation of both Lys residues, suggesting that either one can bind ATP. Mutation of Glu209 (PK catalytic motif III) virtually abrogated kinase activity in the presence of Mg2+ or Mn2+ ions, suggesting that Glu209 functions in ion-dependent PK activity. ICP10 bound the adaptor protein Grb2 in vitro. Mutation of the ICP10 proline-rich motifs at positions 396 and 149 reduced Grb2 binding 20- and 2-fold, respectively. Binding was abrogated by mutation of both motifs. Grb2 binding to wild type ICP10 was competed by a peptide for the Grb2 C-terminal SH3 motif, indicating that it involves the Grb2 C-terminal SH3.
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PMID:ATP and SH3 binding sites in the protein kinase of the large subunit of herpes simplex virus type 2 of ribonucleotide reductase (ICP10). 866 76


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