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)

The G(i)-linked adenosine A1 receptor has been shown to mediate anti-inflammatory actions, possibly via modulation of the transcription factor nuclear factor-kappaB (NFkappaB). Here we demonstrate that an adenosine A1 agonist, N(6)-cyclohexyladenosine (CHA), activated IKKalpha/beta phosphorylation through PTX-insensitive G proteins in human lymphoblastoma Reh cells. To delineate the mechanism of action, different PTX-insensitive G proteins were expressed in human embryonic kidney 293 cells. Only Galpha(16) supported the CHA-induced IKK phosphorylation and NFkappaB-driven luciferase activity in time-dependent, dose-dependent, and PTX-insensitive manners. Gbetagamma subunits also modulated IKK/NFkappaB, as indicated by the stimulatory actions of Gbeta(1)gamma(2) and the abrogation of CHA-induced response by transducin. The participation of phospholipase Cbeta, protein kinase C, and calmodulin-dependent kinase II in CHA-induced IKK/NFkappaB activation were demonstrated by employing specific inhibitors and dominant-negative mutants. Inhibition of c-Src and numerous intermediates along the extracellular signal-regulated (ERK) kinase cascade including Ras, Raf-1 kinase, and MEK1/2 abolished the CHA-induced IKK/NFkappaB activation. Although c-Jun N-terminal kinase and p38 MAPK were also activated by CHA, they were not required for the IKK/NFkappaB regulation. Similar results were obtained using Reh cells. These data suggest that the G(16)-mediated activation of IKK/NFkappaB by CHA required a complex signaling network composed of multiple intermediates.
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PMID:G16-mediated activation of nuclear factor kappaB by the adenosine A1 receptor involves c-Src, protein kinase C, and ERK signaling. 1548 65

The chimeric anti-CD20 antibody rituximab (Rituxan, IDEC-C2B8) is widely used in the clinical treatment of patients with non-Hodgkin's lymphoma (NHL). Rituximab sensitizes NHL B-cell lines to drug-induced apoptosis via down-regulation of Bcl-x(L) expression. We hypothesized that the mechanism by which rituximab down-regulates Bcl-x(L) may be, in part, due to inhibition of constitutive nuclear factor-kappaB (NF-kappaB) activity that regulates Bcl-x(L) expression. This hypothesis was tested in CD20(+) drug-resistant Ramos (Bcl-2(-)/Bcl-x(L)(+)) and Daudi (Bcl-2(+)/Bcl-x(L)(+)) cell lines. Rituximab decreased the phosphorylation of NF-kappaB-inducing kinase, IkappaB kinase, and IkappaB-alpha, diminished IKK kinase activity, and decreased NF-kappaB DNA binding activity. These events occurred with similar kinetics and were observed 3 to 6 hours post-rituximab treatment. Rituximab significantly up-regulated Raf-1 kinase inhibitor protein expression, thus interrupting the NF-kappaB signaling pathway concomitant with Bcl-x(L) and Bfl-1/A1 down-regulation. The role of NF-kappaB in the regulation of Bcl-x(L) transcription was shown using promoter reporter assays in which deletion of the two-tandem NF-kappaB binding sites in the upstream promoter region significantly reduced the luciferase activity. This was further corroborated by using IkappaB superrepressor cells and by NF-kappaB-specific inhibitors. The direct role of Bcl-x(L) in drug resistance was assessed by using Bcl-x(L)-overexpressing cells, which exhibited higher drug resistance that was partially reversed by rituximab. Rituximab-mediated inhibition of the NF-kappaB signaling pathway and chemosensitization was corroborated by the use of specific inhibitors. These findings reveal a novel pathway mediated by rituximab through Raf-1 kinase inhibitor protein induction that negatively regulates the constitutive NF-kappaB pathway and chemosensitization of the NHL B-cells.
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PMID:Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin's lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. 1566 3

Signaling by TNF-family receptor CD40 involves TRAF-family adaptor proteins, leading to activation of protein kinases that induce NFkappaB-family transcription factors. We report here that mitogen activated protein kinase kinase kinase-8 (MAP3K8), Tpl2/COT1, is recruited to the CD40 complex via a mechanism dependent on TRAF-binding sites in CD40. Tpl2/COT1 was shown to participate in CD40 signaling based on the ability of a catalytically inactive mutant to suppress CD40-mediated IkappaB kinase activation and induction of NFkappaB-responsive promoters, without affecting signaling by TNF. Tpl2 (-/-) fibroblasts were also deficient in CD40 but not TNF signaling, further supporting a unique role for Tpl2 in CD40 signaling. Experiments using dominant-negative Tpl2 suggest this kinase functions distal to TRAFs but proximal to the TAK1/TAB1 signaling complex, within the IKK/NFkappaB activation pathway. These results indicate a distinction between TNF Receptor family members CD40 and TNFR1 in their utilization of MAP3Ks, and demonstrate TRAF-dependence of Tpl2 association with the CD40 receptor complex.
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PMID:TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. 1567 Jul 70

Serum and glucocorticoid inducible protein kinase (SGK) plays a crucial role in promoting cell survival, but the mechanisms for this response are not clear. We show that SGK is involved in the regulation of apoptosis in breast cancer cells by modulating the transcriptional activity of nuclear transcription factor kappaB (NF-kappaB). High levels of SGK expression were observed in human breast cancer samples. When SGK was reduced the apoptotic rate increased, and increased SGK activity prevents serum withdrawal-induced apoptosis. SGK-induced cell survival was abolished by a dominant-negative form of IkappaB kinase beta (IKKbeta, K44A) or a null mutation of IKKbeta in mouse embryonic fibroblast cells indicating involvement of the NF-kappaB pathway. Serum-induced SGK or increased expression of SGK activated NF-kappaB transcriptional activity, whereas small interference RNA to SGK blocked NF-kappaB activity. Coexpression of SGK and IKKbeta significantly increased the activation of NF-kappaB (versus expression of IKKbeta alone). Expression of dominant-negative IKKbeta K44A, IkappaBalpha AA, and kinase-dead SGK (127KM) blocked the ability of SGK to stimulate NF-kappaB activity, suggesting that IKKbeta is a target of SGK. We also show that SGK enhances the ability of IKKbeta to phosphorylate endogenous IkappaBalpha in cells or recombinant glutathione S-transferase-IkappaBalpha in vitro and increases IkappaBalpha degradation; SGK physically associates with and activates IKKbeta in MDA231 cells via phosphorylation of Ser(181) in IKKbeta. Taken together, we conclude that SGK acts as an oncogene in breast cancer cells through activation of the IKK-NF-kappaB pathway, thereby preventing apoptosis. Blocking SGK expression/activity represents a potential therapeutic approach for breast cancer treatment.
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PMID:Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase. 1569 87

The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms. First, a transient interaction involving the exchange of lipids between the two interacting cells ('the kiss of death') may lead to the selective death of single CD4-expressing target cells. Second, fusion of the interacting cells may lead to the formation of syncytia which then succumb to apoptosis in a complex pathway involving the activation of several kinases (cyclin-dependent kinase-1, Cdk1; checkpoint kinase-2, Chk2; mammalian target of rapamycin, mTOR; p38 mitogen-activated protein kinase, p38 MAPK; inhibitor of NF-kappaB kinase, IKK), as well as the activation of several transcription factors (NF-kappaB, p53), finally resulting in the activation of the mitochondrial pathway of apoptosis. Third, if the Env-expressing cell is at an early stage of imminent apoptosis, its fusion with a CD4-expressing target cell can precipitate the death of both cells, through a process that may be considered as contagious apoptosis and which does not involve Cdk1, mTOR, p38 nor p53, yet does involve mitochondria. Activation of some of the above- mentioned lethal signal transducers have been detected in patients' tissues, suggesting that HIV-1 may indeed trigger apoptosis through molecules whose implication in Env-induced killing has initially been discovered in vitro.
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PMID:Mechanisms of apoptosis induction by the HIV-1 envelope. 1571 26

Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor kappaB (NF-kappaB) through IkappaB kinase beta (IKKbeta), but a negative role in the noncanonical pathway that activates NF-kappaB through IKKalpha. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K(63) polyubiquitin chains, but is targeted to degradation by the proteasome when it is K(48)-polyubiquitinted by the NF-kappaB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.
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PMID:TRAF2: a double-edged sword? 1572 25

Aberrant activation of nuclear factor-kappaB (NF-kappaB) transcription factors has been implicated in the pathogenesis of breast cancer. We previously showed elevated activity of IkappaB kinase alpha (IKKalpha), IKKbeta, and protein kinase CK2 in primary human breast cancer specimens and cultured cells. A novel inducible IKK protein termed IKK-i/IKKepsilon has been characterized as a potential NF-kappaB activator. Here, we provide evidence that implicates IKK-i/IKKepsilon in the pathogenesis of breast cancer. We show IKK-i/IKKepsilon expression in primary human breast cancer specimens and carcinogen-induced mouse mammary tumors. Multiple breast cancer cell lines showed higher levels of IKK-i/IKKepsilon and kinase activity compared with untransformed MCF-10F breast epithelial cells. Interestingly, IKK-i/IKKepsilon expression correlated with CK2alpha expression in mammary glands and breast tumors derived from MMTV-CK2alpha transgenic mice. Ectopic CK2 expression in untransformed cells led to increased IKK-i/IKKepsilon mRNA and protein levels. Inhibition of CK2alpha via the pharmacologic inhibitor apigenin or upon transfection of a CK2 kinase-inactive subunit reduced IKK-i/IKKepsilon levels. Expression of a kinase-inactive IKK-i/IKKepsilon mutant in breast cancer cells reduced NF-kappaB activity as judged by transfection assays of reporters driven either by NF-kappaB elements or the promoters of two NF-kappaB target genes, cyclin D1 and relB. Importantly, the kinase-inactive IKK-i/IKKepsilon mutant reduced the endogenous levels of these genes as well as the ability of breast cancer cells to grow in soft agar or form invasive colonies in Matrigel. Thus, CK2 induces functional IKK-i/IKKepsilon, which is an important mediator of the activation of NF-kappaB that plays a critical role in the pathogenesis of breast cancer.
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PMID:Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells. 1635 45

Hepatitis C virus (HCV) NS5B protein is a membrane-associated phosphoprotein that possesses an RNA-dependent RNA polymerase activity. We recently reported that NS5A protein interacts with TRAF2 and modulates tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB and Jun N-terminal protein kinase (JNK). Since NS5A and NS5B are the essential components of the HCV replication complex, we examined whether NS5B could modulate TNF-alpha-induced NF-kappaB and JNK activation. In this study, we have demonstrated that TNF-alpha-induced NF-kappaB activation is inhibited by NS5B protein in HEK293 and hepatic cells. Furthermore, NS5B protein inhibited both TRAF2- and IKK-induced NF-kappaB activation. Using coimmunoprecipitation assays, we show that NS5B interacts with IKKalpha. Most importantly, NS5B protein in HCV subgenomic replicon cells interacted with endogenous IKKalpha, and then TNF-alpha-mediated IKKalpha kinase activation was significantly decreased by NS5B. Using in vitro kinase assay, we have further found that NS5B protein synergistically activated TNF-alpha-mediated JNK activity in HEK293 and hepatic cells. These data suggest that NS5B protein modulates TNF-alpha signaling pathways and may contribute to HCV pathogenesis.
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PMID:Hepatitis C virus nonstructural 5B protein regulates tumor necrosis factor alpha signaling through effects on cellular IkappaB kinase. 1658 80

The interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) has been shown to activate NF-kappaB independently of its kinase function after interaction with the IKK complex. In order to investigate the mechanism of NF-kappaB activation by PKR, we identified the domain of PKR responsible for stimulating the NF-kappaB pathway in PKR-deficient fibroblasts using an NF-kappaB dependent reporter assay. The N-terminal 1-265 AA of PKR activates NF-kappaB, whereas the 1-180 AA N-terminus restricted to the two dsRNA Binding Domains (DRBD), the third basic domain alone (AA 181-265), or the C-terminus of PKR (AA 266-550) were unable to stimulate the expression of the NF-kappaB dependent reporter gene. Using confocal microscopy, we confirmed that PKR full length as well as PKR N-terminus colocalized with IKKbeta. By GST-pulldown analysis, using different PKR domains, we then revealed the specific ability of the PKR N-terminus 1-265 to bind to and activate IKK and showed that this activation requires the integrity of the IKK complex. This activation is not only due to DRBDs since the DRBD fragment 1-180 failed to inhibit PKR 1-265 induced NF-kappaB activation. Our results therefore demonstrate that the ability of PKR to mediate NF-kappaB activation resides in its full N-terminus, and requires both DRBDs and the third basic domain.
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PMID:The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex. 1660 May 70

Phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B (NF-kappaB) signaling pathways play a critical role in mediating survival signals. In this study we have investigated how loss of dystrophin (the primary cause of Duchenne muscular dystrophy) modulates the activation of PI3K/Akt and NF-kappaB signaling pathways in skeletal muscle in response to mechanical stimulation. Activation of Akt was significantly higher in diaphragm muscle from dystrophin-deficient mdx mice compared to normal mice at both prenecrotic and necrotic states. Higher activation of Akt was also observed in cultured dystrophin-deficient primary myotubes differentiated in vitro. Application of passive mechanical stretch ex vivo synergistically increased the activation of Akt in diaphragm of mdx mice. Stretch-induced activation of PDK-1 and PI3K were also higher in diaphragm of mdx mice compared to normal mice. Pretreatment of diaphragm with PI3K inhibitor LY294002 blocked the activation of Akt in normal and mdx mice. Higher activation of Akt was associated with increased phosphorylation of its downstream targets glycogen synthase kinase 3beta (GSK3beta), FKHR, and mammalian target of rapamycin (mTOR). Treatment of diaphragm muscle with LY294002 inhibited the stretch-induced activation of IkappaB (IkappaB) kinase (IKK) and NF-kappaB transcription factor in normal and mdx mice. Mechanical stretch also reduced the interaction of HDAC1 with RelA subunit of NF-kappaB in diaphragm muscle. Finally, cellular levels of Bcl-2, cIAP1, and integrin beta1 and activation of integrin linked kinase were higher in diaphragm muscle of mdx mice compared to normal mice. Taken together, our data suggest that loss of dystrophin and/or mechanical stretch results in the up-regulation of P13K/Akt and NF-kappaB signaling pathways in skeletal muscle.
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PMID:Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch. 1674 26


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