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)

One of the earliest events following T cell receptor (TCR) triggering is the activation of the protein kinase Lck and induction of tyrosine phosphorylation of zeta, the major signal transduction subunit of the T cell receptor complex. Here we report the generation and characterization of a monoclonal antibody specific for human phosphozeta. The antibody was produced by immunizing mice with a truncated recombinant form of human zeta together with the Lck enzyme. The C415.9A antibody recognizes recombinant as well as cellular phosphozeta but is unreactive with unphosphorylated zeta or other tyrosine phosphorylated proteins. Using this antibody, we have demonstrated aberrant TCR-zeta tyrosine phosphorylation in Jurkat T cell transduction mutants. Therefore, this antibody can be used to elucidate T cell signal transduction mechanisms by analyzing and monitoring tyrosine phosphorylation of zeta in vitro and in vivo directly. Furthermore, this antibody could find application in the analysis of abnormal T cell signaling in autoimmune disease, cancer, and immunodeficiency disorders.
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PMID:Production and characterization of a novel monoclonal antibody against phosphorylated T cell receptor zeta chain. 914 19

The human immunodeficiency virus type 1 matrix (MA) protein is phosphorylated during virion maturation on its C-terminal tyrosine and on several serine residues. Whereas MA tyrosine phosphorylation facilitates viral nuclear import, the significance of MA serine phosphorylation remains unclear. Here, we report that MA serine but not tyrosine phosphorylation is strongly enhanced by Nef. Mutations that abrogated the membrane association of Nef and its ability to bind a cellular serine/threonine kinase greatly diminished the extent of virion MA serine phosphorylation. Correspondingly, a protein kinase coimmunoprecipitated with Nef could phosphorylate MA on serine in vitro, producing a phosphopeptide pattern reminiscent of that of virion MA. Recombinant p21-activated kinase hPAK65, a recently proposed relative of the Nef-associated kinase, achieved a comparable result. Taken together, these data suggest that MA is a target of the Nef-associated serine kinase.
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PMID:The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix. 915 26

Here we report the presence of a protein kinase activity associated with human immunodeficiency virus type 1 (HIV-1) particles. We observed phosphorylation of five major proteins by the endogenous protein kinase activity. Phosphoamino acid analysis revealed phosphorylated serine and threonine residues. In addition, we observed autophosphorylation of two proteins in the presence of gamma-ATP in an in-gel phosphorylation assay. These two proteins are not linked by a disulfide bond, suggesting that two different protein kinases are associated with HIV-1 virions. Our results indicate the presence of ERK2 mitogen-activated protein kinase and of a 53,000-molecular-weight protein kinase associated with virions. Moreover, the use of different HIV strains derived from T cells and promonocytic cells, as well as the use of human T-cell leukemia virus type 1 particles, demonstrates that ERK2 is strongly associated with retrovirus particles in a cell-independent manner. Exogenous substrates, such as histone proteins, and a viral substrate, such as Gag protein, are phosphorylated by virus-associated protein kinases.
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PMID:Association of ERK2 mitogen-activated protein kinase with human immunodeficiency virus particles. 915 81

Alterations in protein kinase C (PKC) activity have been implied in the pathogenesis of common variable immunodeficiency (CVID). We analyzed amiloride-sensitive red blood cell Na+/H+ exchange (sodium-proton antiport, SPA) and its response to protein kinase stimulation in a patient with CVID. Compared with healthy subjects or patients with sepsis, a unique pattern of SPA activation has been shown. The patient's SPA was decreased and unresponsive to PKC stimulation, whereas stimulation by insulin, a tyrosine kinase activator, restored SPA activity. An alteration of serine-threonine phosphorylation is suggested as a possible mechanism for the immune failure.
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PMID:Common variable immunodeficiency associated with myelocathexis and altered membrane sodium-proton antiport. 920 Jan 89

Activating protein-1 (AP-1) binding phorbol ester responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind cFos and junD and transmit protein kinase C (PKC) activation signals to the LTR. Further studies suggested the DSE might also bind AP-1-related proteins of the CREB/ATF family. Since enhanced HIV-1 expression is associated with activation of the cAMP-dependent protein kinase A (PKA) signaling pathway, we determined whether binding of CREB/ATF proteins to the DSE mediate cAMP/PKA activation of the HIV-1 LTR. In the present study. DSE binding complexes in nuclear protein extracta from colonic epithelial cells are shown to contain ATF-1, ATF-2, and CREB and transfection of either an ATF-2 or PKA expressing plasmid transactivated the DSE. Cholera toxin (Ctx), a potent activator of the cAMP/PKA pathway. Increased HIV-1 virus production from a latently infected promonocytic cell line, U1. Ctx increased LTR promoter activity and increased the CREB content of DSE binding complexes. Transfection of U1 cells with a series of mutant LTR reporter constructs demonstrated that the Ctx response was in large part mediated by the DSE. The Ctx response was also mediated by a heterologous promoter containing multiple TRE sites. Nuclear protein extracts from a T-cell line infected by HIV-1 contained higher levels of CREB/ATF proteins and manifested increased CREB/ATF binding activity. Collectively, these results indicate the DSE are TRE-like cAMP responsive elements that bind both AP-1 and CREB/ATF permitting induction of the HIV-1 LTR by both PKC and PKA activation signals.
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PMID:U5 region of the human immunodeficiency virus type 1 long terminal repeat contains TRE-like cAMP-responsive elements that bind both AP-1 and CREB/ATF proteins. 920 Dec 33

We have cloned and characterized Xlrbpa, a double-stranded RNA-binding protein from Xenopus laevis. Xlrbpa is a protein of 33 kD and contains three tandemly arranged, double-stranded RNA-binding domains (dsRBDs) that bind exclusively to double-stranded RNA in vitro, but fail to bind either single-stranded RNA or DNA. Sequence data and the overall organization of the protein suggest that Xlrbpa is the Xenopus homologue of human TAR-RNA binding protein (TRBP), a protein isolated by its ability to bind to human immunodeficiency virus (HIV) TAR-RNA. In transfection assays, TRBP has also been shown to inhibit the interferon-induced protein kinase PKR possibly by direct physical interaction. To determine the function of Xlrbpa and its human homologue we studied the expression and intracellular distribution of the two proteins. Xlrbpa is ubiquitously expressed with marked quantitative differences amongst all tissues. Xlrbpa and human TRBP can be detected in the cytoplasm and nucleus by immunofluorescence staining and Western blotting. Sedimentation gradient analyses and immunoprecipitation experiments suggest an association of cytoplasmic Xlrbpa with ribosomes. In contrast, a control construct containing two dsRBDs fails to associate with ribosomes in microinjected Xenopus oocytes. Nuclear staining of Xenopus lampbrush chromosome preparations showed the association of the protein with nucleoli, again indicating an association of the protein with ribosomal RNAs. Additionally, Xlrbpa could be located on lampbrush chromosomes and in snurposomes. Immunoprecipitations of nuclear extracts demonstrated the presence of the protein in heterogeneous nuclear (hn) RNP particles, but not in small nuclear RNPs, explaining the chromosomal localization of the protein. It thus appears that Xlrbpa is a general double-stranded RNA-binding protein which is associated with the majority of cellular RNAs, ribosomal RNAs, and hnRNAs either alone or as part of an hnRNP complex.
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PMID:Xlrbpa, a double-stranded RNA-binding protein associated with ribosomes and heterogeneous nuclear RNPs. 923 68

During virus assembly, a subset of human immunodeficiency virus (HIV) matrix (MA) molecules is phosphorylated on C-terminal tyrosine. This modification facilitates infection of nondividing cells by allowing for the recruitment of the karyophilic MA into the viral core and preintegration complex. MA tyrosine phosphorylation is accomplished by a cellular protein kinase which is incorporated into virions. In this study, we have investigated the nature of this enzyme as well as the determinants of MA necessary for its phosphorylation. Employing an in vitro kinase assay, we found that the MA tyrosine kinase activity is present in various cultured cell lines including CEM and SupT1 T-lymphoid cells, Namalwa B cells, 293 and CV-1 kidney fibroblasts, and P4 HeLa cells. In addition, it could be detected in platelets, macrophages, and activated peripheral blood lymphocytes (PBLs) but not in erythrocytes and resting PBLs isolated from human blood. Subcellular localization of the kinase activity by cell fractionation demonstrated that it is enriched in cellular membranes. In HIV type 2 (HIV-2) particles, the MA tyrosine kinase is associated with the inner leaflet of the viral membrane, while the tyrosine-phosphorylated MA is localized to the core. Individual mutations of each of the last eight residues immediately upstream of the C-terminal tyrosine (Y132) of HIV-1 MA did not prevent Y132 phosphorylation, suggesting that the kinase does not require a highly specific sequence adjacent to the C-terminal tyrosine. Confirming this, we found that the MA of murine leukemia virus, the sequence of which is only moderately homologous to that of HIV-1 and HIV-2 MA, is also C-terminally tyrosine phosphorylated.
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PMID:Human immunodeficiency virus matrix tyrosine phosphorylation: characterization of the kinase and its substrate requirements. 926 8

Human immunodeficiency virus (HIV) infection may cause a dementing illness. HIV-mediated dementia is clinically and pathologically correlated with the infiltration of activated macrophages and elevated levels of tumor necrosis factor (TNF)-alpha, both of which occur in an environment of small numbers of infected cells. We examined the possibility that HIV protein Tat, which is released extracellularly from infected cells, may induce the production of TNF-alpha. Tat induced TNF-alpha mRNA and protein production dose-dependently, primarily in macrophages but also in astrocytic cells. The TNF-alpha induction was NF-kappaB-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF-alpha release was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial cell activation and suggest new therapeutic approaches for HIV dementia.
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PMID:The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases. 927 85

Human immunodeficiency virus (HIV)-1 expression in mononuclear phagocytes is associated with multiple functional defects, including phagocytosis. To assess Fcgamma receptor (FcgammaR) function in cells expressing HIV-1, human promonocytic cells (U937) acutely or chronically infected with HIV-1, or stably transfected with a noninfectious reverse transcriptase (RT) defective HIV-1 provirus (Deltapol), were treated with phorbol 12-myristate 13-acetate for 48 hours and tested for their ability to ingest sheep erythrocytes coated with IgG (E-IgG). HIV-1-infected or transfected U937 cells ingested 50% to 65% fewer E-IgG than controls despite normal surface expression of FcgammaRs. HIV-1 specifically impaired FcgammaR-mediated phagocytosis, as ingestion of complement-coated erythrocytes was unaffected. U937 cells transfected with an env deficient mutant of HIV-1 ingested E-IgG normally, suggesting that the expression of HIV-1 env was required for HIV-1 to inhibit FcgammaR-mediated phagocytosis. Expression of HIV-1 in U937 cells was associated with an increased accumulation of intracellular cyclic adenosine monophosphate (cAMP); addition of the adenylate cyclase inhibitor 2',5'-dideoxyadenosine to these cells decreased intracellular cAMP levels to that of controls and restored FcgammaR-mediated phagocytosis. Addition of either interferon (IFN)-gamma or an inhibitor of cAMP-dependent protein kinase A (KT 5720) to HIV-1-transfected U937 cells also restored FcgammaR-mediated phagocytosis. Expression of HIV-1 induces a specific defect of FcgammaR function in mononuclear phagocytes that correlates with increased levels of cAMP, and can be corrected by pharmacologic manipulation.
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PMID:Human immunodeficiency virus-1 env impairs Fc receptor-mediated phagocytosis via a cyclic adenosine monophosphate-dependent mechanism. 934 63

Equine combined immunodeficiency disease (CID) is caused by homozygosity for an autosomal recessive gene. To identify linked markers for the disease, we studied a family segregating for the equine CID gene. A stallion and 19 of his CID-affected offspring were tested for marker segregation at 23 microsatellite DNA loci. His CID-affected offspring inherited only one of his two alleles at the HTG8 and HTG4 loci, namely HTG8-186 and HTG4-124, respectively. Lod scores for linkage to the CID gene using a theta of 0.01 were 5.34 for HTG8 and 2.37 for HTG4. The apparent genotypes also suggested linkage disequilibrium between the HTG8-186 allele and the gene for CID. The gene for the DNA protein kinase catalytic subunit (DNA-PK) was recently suggested as a candidate gene for equine CID. A defect of this gene causes a disease in mice that is similar to equine CID. Therefore, we investigated whether this gene might be associated with the microsatellite markers. Analysis of a somatic cell hybrid panel demonstrated synteny of DNA-PK with HTG4 and HTG8 (Kentucky Synteny Group 3). Fluorescence in situ hybridization (FISH) studies demonstrated that DNA-PK is located on horse chromosome ECA9p12. This work supports the hypothesis of DNA-PK as the probable cause of equine CID.
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PMID:Linkage of the gene for equine combined immunodeficiency disease to microsatellite markers HTG8 and HTG4; synteny and FISH mapping to ECA9. 934 23


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