Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha-, beta-, and gamma-Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpesviruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpesvirus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.
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PMID:ORF36 protein kinase of Kaposi's sarcoma herpesvirus activates the c-Jun N-terminal kinase signaling pathway. 1524 71

Infection of endothelial cells with human herpesvirus 8 (HHV-8) is an essential event in the development of Kaposi's sarcoma. When primary microvascular endothelial cells (MECs) were infected with HHV-8 at a low multiplicity of infection, considerable latent replication of HHV-8 occurred, leading to a time-dependent increase in the percentage of virus-infected cells that was accompanied by cellular spindling and growth to a high density with loss of contact inhibition. Only a low percentage of MECs supported lytic replication of HHV-8 and produced infectious virus. Phosphonoformic acid blocked production of infectious virus but did not inhibit the rapid expansion of latently infected MECs. Pretreatment of MECs with alpha interferon (IFN-alpha) prior to infection effectively reduced HHV-8 viral gene expression, latent replication, and production of infectious virus. High levels of the double-stranded RNA activated protein kinase (PKR) were expressed in HHV-8-infected cells, and incubation with IFN-alpha increased PKR expression more in virus-infected cells than in uninfected cells. MECs that were immortalized with simian virus 40 large-T antigen differed from nonimmortalized MECs in their response to infection with HHV-8 and demonstrated that cells with elevated levels of expression of antiviral transcripts expressed viral transcripts at reduced levels. These studies demonstrate that MECs respond to HHV-8 with enhanced expression of cellular antiviral genes and that augmentation of innate antiviral defenses with IFN-alpha is a more effective strategy than inhibition of viral lytic replication to protect MECs from infection with HHV-8 and to restrict proliferation of virus-infected MECs.
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PMID:Inhibition of infection and replication of human herpesvirus 8 in microvascular endothelial cells by alpha interferon and phosphonoformic acid. 1525 8

Human herpesvirus-8 (HHV-8) is aetiologically linked to Kaposi's sarcoma and primary effusion lymphoma. Although interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) are both antiviral cytokines, IFN-alpha blocks entry of HHV-8 into the lytic phase, whereas IFN-gamma induces an increase in the percentage of cells undergoing lytic replication. Multiple events in the lytic cascade must be completed to produce infectious virus. The ability of both types of IFN to affect the production of infectious virus was explored. Both IFN-alpha and IFN-gamma induced expression of the antiviral proteins double-stranded RNA-activated protein kinase (PKR) and 2'5'-oligoadenylate synthetase (2'5'-OAS) in HHV-8-infected BCBL-1 cells. Higher levels resulted from incubation with IFN-alpha than with IFN-gamma, whereas IFN-gamma induced higher levels of IRF-1 than did IFN-alpha. IFN-gamma induced a minor increase in lytic viral gene expression, which was not accompanied by a detectable increase in infectious virus. When lytic replication of HHV-8 was induced using TPA, high levels of infectious virus appeared in the conditioned medium. When IFN-gamma was present during TPA stimulation, the production of infectious virus was reduced by at least a 60 %, and IFN-alpha fully blocked TPA-induced production of infectious virus. The greater reduction of viral production that occurred with IFN-alpha is consistent with the higher levels of the antiviral proteins PKR and 2'5'-OAS induced by IFN-alpha than by IFN-gamma. These studies indicate that the augmentation of cellular antiviral defences by IFN-gamma was sufficient to prevent production of infectious virus despite IFN-gamma-induced entry of some cells into the lytic phase of HHV-8 replication.
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PMID:Inhibition of infectious human herpesvirus 8 production by gamma interferon and alpha interferon in BCBL-1 cells. 1544 38

ORF57 protein of Kaposi's sarcoma-associated herpesvirus has a counterpart in all herpesvirus of mammals and birds and regulates gene expression at transcriptional and post-transcriptional levels. ORF57 was capable of self-interaction and bound a rapidly migrating form of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a multifunctional cellular protein involved in gene expression. In virus infected cell extracts, ORF57 was present in a complex with hnRNP K that had protein kinase CK2 activity, and was phosphorylated by CK2. Different regions of ORF57 bound both catalytic alpha/alpha' and regulatory beta subunits of CK2. CK2 modification enhanced the ORF57-hnRNP K interaction, and may regulate the presence and activities of components in the complex. We suggest that ORF57 and hnRNP K interaction may modulate ORF57-mediated regulation of viral gene expression. Herpesviral ORF57 (Rhadinovirus) and ICP27 (Simplexvirus) proteins both interact with hnRNP K and CK2 implying that adaptation of the ancestral hnRNP K and CK2 to associate with viral regulatory ancestor protein likely pre-dates divergence of these Herpesviridae genera that occurred 200 million years ago.
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PMID:Protein kinase CK2 phosphorylation regulates the interaction of Kaposi's sarcoma-associated herpesvirus regulatory protein ORF57 with its multifunctional partner hnRNP K. 1548 5

The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein stabilizes beta-catenin by the novel mechanism of binding to the negative regulator, glycogen synthase kinase 3 (GSK-3), and depleting cytoplasmic GSK-3 levels. The two domains of LANA required for interaction with GSK-3 were further characterized. Evidence for similarity between the C-terminal LANA interaction domain and the axin GSK-3 interaction domain was obtained using GSK-3 and LANA mutants. GSK-3(F291L), which does not interact with axin, also failed to bind to LANA, and a mutation in the axin homology domain of LANA, L1132P, destroyed binding to GSK-3. The N-terminal LANA interaction domain was found to mediate interaction by acting as a substrate for GSK-3. GSK-3(R96A), a priming pocket mutant, did not bind to LANA, suggesting that LANA was a primed GSK-3 substrate. Phosphorylation of endogenous LANA precipitated from primary effusion lymphoma cells was inhibited by the GSK-3 inhibitor LiCl. GST-LANA(1-340) was phosphorylated by GSK-3, and mitogen-activated protein kinase (MAPK) and casein kinase I functioned as priming kinases in vitro. Mutation of consensus GSK-3 sites revealed that sites between LANA amino acids 219 and 268 were important for GSK-3 phosphorylation. Immunoprecipitation assays revealed that loss of GSK-3 phosphorylation of this N-terminal domain correlated with loss of GSK-3 interaction. Although LANA-associated GSK-3 actively phosphorylated LANA, GSK-3 coprecipitated with LANA was unable to phosphorylate an exogenous peptide substrate. LANA sequestration of GSK-3 may explain the ability of KSHV-infected cells to tolerate increased levels of nuclear GSK-3.
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PMID:Regulation of the interaction between glycogen synthase kinase 3 and the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen. 1605 35

Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication is mediated by the viral RTA transcription factor, but little is known about the physiological processes controlling its expression or activity. Links between autonomic nervous system activity and AIDS-associated Kaposi's sarcoma led us to examine the potential influence of catecholamine neurotransmitters. Physiological concentrations of epinephrine and norepinephrine efficiently reactivated lytic replication of KSHV in latently infected primary effusion lymphoma cells via beta-adrenergic activation of the cellular cyclic AMP/protein kinase A (PKA) signaling pathway. Effects were blocked by PKA antagonists and mimicked by pharmacological and physiological PKA activators (prostaglandin E2 and histamine) or overexpression of the PKA catalytic subunit. PKA up-regulated RTA gene expression, enhanced activity of the RTA promoter, and posttranslationally enhanced RTA's trans-activating capacity for its own promoter and heterologous lytic promoters (e.g., the viral PAN gene). Mutation of predicted phosphorylation targets at RTA serines 525 and 526 inhibited PKA-mediated enhancement of RTA trans-activating capacity. Given the high catecholamine levels at sites of KSHV latency such as the vasculature and lymphoid organs, these data suggest that beta-adrenergic control of RTA might constitute a significant physiological regulator of KSHV lytic replication. These findings also suggest novel therapeutic strategies for controlling the activity of this oncogenic gammaherpesvirus in vivo.
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PMID:beta-Adrenoreceptors reactivate Kaposi's sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. 1622 74

Kaposi's sarcoma-associated herpesvirus (KSHV) is the latest addition to the long list of human herpesviruses. Reactivation of latent herpesvirus infections is still a mystery. It was demonstrated recently that the phorbol ester TPA was efficient in inducing a reactivation of KSHV infection in the S phase of the cell cycle. In the present study, flow cytometry-sorted, TPA-induced, KSHV-infected haematopoietic cells (BCBL-1) were used to analyse the expression profiles of cancer-related cellular genes in the S phase of the cell cycle compared with the G0/1 phase by using microarrays. Overall, the S phase of the cell cycle seems to provide KSHV with an apt environment for a productive lytic cycle of infection. The apt conditions include cellular signalling that promotes survivability, DNA replication and lipid metabolism, while blocking cell-cycle progression to M phase. Some of the important genes that were overexpressed during the S phase of the cell cycle compared with the G0/1 phase of TPA-induced BCBL-1 cells are v-myb myeloblastosis (MYBL2), protein kinase-membrane associated tyrosine/threonine 1 (PKMYT1), ribonucleotide reductase M1 polypeptide (RRM1) and peroxisome proliferator-activated receptors delta (PPARD). Inhibition of PKMYT1 expression by the use of specific short interfering RNAs significantly lowered the TPA-induced KSHV lytic cycle of infection. The significance of these and other genes in the reactivation of KSHV is discussed in the following report. Taken together, a flow cytometry-microarray-based method to study the cellular conditions critical for the reactivation of KSHV infection is reported here for the first time.
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PMID:Identifying cellular genes crucial for the reactivation of Kaposi's sarcoma-associated herpesvirus latency. 1647 73

K cyclin encoded by Kaposi's sarcoma-associated herpesvirus confers resistance to the cyclin-dependent kinase (cdk) inhibitors p16Ink4A, p21Cip1, and p27Kip1 on the associated cdk6. We have previously shown that K cyclin expression enforces S-phase entry on cells overexpressing p27Kip1 by promoting phosphorylation of p27Kip1 on threonine 187, triggering p27Kip1 down-regulation. Since p21Cip1 acts in a manner similar to that of p27Kip1, we have investigated the subversion of a p21Cip1-induced G1 arrest by K cyclin. Here, we show that p21Cip1 is associated with K cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the K cyclin/cdk6 complex, resulting in phosphorylation of p21Cip1 on serine 130. This phosphoform of p21Cip1 appeared unable to associate with cdk2 in vivo. We further demonstrate that phosphorylation on serine 130 is essential for K cyclin-mediated release of a p21Cip1-imposed G1 arrest. Moreover, we show that under physiological conditions of cell cycle arrest due to elevated levels of p21Cip1 resulting from oxidative stress, K cyclin expression enabled S-phase entry and was associated with p21Cip1 phosphorylation and partial restoration of cdk2 kinase activity. Thus, expression of the viral cyclin enables cells to subvert the cell cycle inhibitory function of p21Cip1 by promoting cdk6-dependent phosphorylation of this antiproliferative protein.
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PMID:Phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1 on serine 130 is essential for viral cyclin-mediated bypass of a p21Cip1-imposed G1 arrest. 1650 17

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3'-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size.
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PMID:Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus. 1658 91

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell-cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.
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PMID:Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. 1663 32


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