Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as well as deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signals leading to IkappaB kinase and NF-kappaB activation. Here we demonstrate that the TCR-independent CD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cell activation factor, but not proliferative (IL-2), genes, in a NF-kappaB-dependent manner. CD28-stimulated T cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis. The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52 NF-kappaB subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-kappaB sites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as a key regulator of genes important for both survival and inflammation.
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PMID:CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-kappaB subunits on IL-8 and Bcl-xL gene promoters. 1507 71

Lipid rafts are detergent-insoluble membrane domains that play a key role in signal transduction by the T-cell antigen receptor. Proteome analysis revealed the presence of amidosulfobetaine-soluble signal transducing, integral membrane, cytoskeletal, heat shock, and GTP-binding proteins in rafts prepared from Jurkat cells. Several of these proteins were recruited to rafts by CD3/CD28 costimulation. Of particular interest is the inducible association of activated IkappaB kinase complexes with raft vesicles that could be captured with anti-flotillin-1 antibodies. Following amidosulfobetaine solubilization, flotillin-beta and IKKbeta underwent reciprocal co-immunoprecipitation. Treatment of Jurkat cells with methyl-beta-cyclodextrin disrupted the assembly and activation of this raft complex and also interfered in CD3/ CD28-induced activation of a NF-kappaB response element in the IL-2 promoter.
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PMID:Proteome analysis of lipid rafts in Jurkat cells characterizes a raft subset that is involved in NF-kappaB activation. 1525 25

Recently, it has been demonstrated that stimulated T cells bearing defects in caspase-8 fail to promote nuclear shuttling of NF-kappaB complexes. Such cells display strikingly similar proliferative and survival defects as T cells lacking Fas-associated death domain protein (FADD) function. We characterized NF-kappaB signaling in T cells bearing a dominant-negative FADD transgene (FADDdd). Whereas FADDdd T cells displayed proliferative defects following activation, these were not a consequence of aberrant NF-kappaB signaling, as measured by IKK/IkappaB phosphorylation and IkappaB degradation. There were no appreciable defects in nuclear translocation of p65/Rel using ImageStream, a flow-based imaging cytometer. Pretreatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a potent caspase inhibitor, also failed to impede canonical NF-kappaB signaling. Secretion of IL-2 and up-regulation of various activation markers occurred normally. Thus, FADD does not play an essential role in NF-kappaB activation, suggesting an alternative route by which this adaptor promotes the clonal expansion of T cells.
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PMID:Cutting edge: FADD is not required for antigen receptor-mediated NF-kappaB activation. 1633 14

Productive engagement of TCR results in delivering signals required for T cell proliferation as well as T cell survival. Blocking TCR-mediated survival signals, T cells undergo apoptosis instead of proliferation upon TCR stimulation. During the activation process, T cells produce IL-2, which acts as an extrinsic survival factor. In addition, TCR stimulation results in up-regulation of Bcl-xL to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-theta is required for enhancing the survival of activated CD4+ T cells by up-regulating Bcl-xL. In response to TCR stimulation, CD4+ PKC-theta-/- T cells failed to up-regulate Bcl-xL, and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC-theta-deficient primary CD4+ T cells, small interfering RNA-mediated knockdown of PKC-theta in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-xL was sufficient to inhibit apoptosis observed in PKC-theta knockdown cells. Furthermore, ectopic expression of PKC-theta stimulated a reporter gene driven by a mouse Bcl-xL promoter. Whereas an inactive form of PKC-theta or knockdown of endogenous PKC-theta led to inhibition of Bcl-xL reporter. PKC-theta-mediated activation of Bcl-xL reporter was inhibited by dominant-negative IkappaB kinase beta or dominant-negative AP-1. Thus, the PKC-theta-mediated signals may function not only in the initial activation of naive CD4+ T cells, but also in their survival during T cell activation by regulating Bcl-xL levels through NF-kappaB and AP-1 pathways.
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PMID:Protein kinase C-theta-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL. 1670 30

T cell receptor (TCR) signaling to IkappaB kinase (IKK)/NF-kappaB is controlled by PKCtheta-dependent activation of the Carma1, Bcl10, and Malt1 (CBM) complex. Antigen-induced phosphorylation of Bcl10 has been reported, but its physiological function is unknown. Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Mutation of the IKKbeta phosphorylation sites on Bcl10 enhances expression of NF-kappaB target genes IL-2 and TNFalpha after activation of primary T cells. Thus, our data provide evidence that IKKbeta serves a dual role upstream of its classical substrates, the IkappaB proteins. While being essential for triggering initial CBM complex formation, IKKbeta-dependent phosphorylation of Bcl10 exhibits a negative regulatory role in T cell activation.
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PMID:Essential role for IkappaB kinase beta in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation. 1681 29

Activation of the transcription factor NF-kappaB after stimulation through antigen receptors is important for lymphocyte differentiation, activation, proliferation, and protection against apoptosis. Much progress has been made in understanding the molecular events leading to NF-kappaB activation, but how this activation is eventually down-regulated is less well understood. Recent studies have indicated that Bcl10 functions downstream of lymphocyte antigen receptors to promote the activation of the IkappaB kinase complex leading to the phosphorylation and degradation of the IkappaB inhibitors of NF-kappaB. Bcl10 has also been implicated in the pathogenesis of mucosa-associated lymphoid tissue lymphoma, possibly in association with its nuclear localization. Here, we provide evidence that the IkappaB kinase complex phosphorylates Bcl10 after T cell antigen receptor stimulation and causes its proteolysis via the beta-TrCP ubiquitin ligase/proteasome pathway. These findings document a negative regulatory activity of the IKK complex and suggest that Bcl10 degradation is part of the regulatory mechanisms that precisely control the response to antigens. Mutants of Bcl10 in the IKK phosphorylation site are resistant to degradation, accumulate in the nucleus, and lead to an increase in IL-2 production after T cell antigen receptor stimulation.
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PMID:Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10. 1721 22

The positive regulation of the NF-kappaB-signaling pathway in response to TCR stimulation has been well-studied. However, little is known about the negative regulation of this pathway in T cells. This negative regulation is crucial in controlling the duration of TCR signaling and preventing abnormal lymphocyte activation and proliferation. Therefore, understanding the negative regulation of TCR-mediated NF-kappaB signaling is essential in understanding the mechanisms involved in T cell function and homeostasis. TCR stimulation of human CD4+ T cells resulted in an increase in NF-kappaB2/p100 expression with no appreciable increase in p52, its cleavage product. Due to the presence of inhibitory ankyrin repeats in the unprocessed p100, this observation suggests that p100 may function as a negative regulator of the NF-kappaB pathway. Consistent with this hypothesis, ectopic expression of p100 inhibited TCR-mediated NF-kappaB activity and IL-2 production in Jurkat T cells. Conversely, knockdown of p100 expression enhanced NF-kappaB transcriptional activity and IL-2 production upon TCR activation. p100 inhibited the pathway by binding and sequestering Rel transcription factors in the cytoplasm without affecting the activity of the upstream IkappaB kinase. The kinetics and IkappaB kinase gamma/NF-kappaB essential modulator dependency of p100 induction suggest that NF-kappaB2/p100 acts as a late-acting negative-feedback signaling molecule in the TCR-mediated NF-kappaB pathway.
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PMID:Negative regulation of TCR signaling by NF-kappaB2/p100. 1754 14

Triggering of antigen receptors on lymphocytes is critical for initiating adaptive immune response against pathogens. T-cell receptor (TCR) engagement induces the formation of the Carma1-Bcl10-Malt1 (CBM) complex that is essential for activation of the IkappaB kinase (IKK)/NF-kappaB pathway. However, the molecular mechanisms that link CBM complex formation to IKK activation remain unclear. Here we report that Malt1 is polyubiquitinated upon T-cell activation. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma. TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Multiple lysine residues in the C-terminus of Malt1 serve as acceptor sites for the assembly of polyubiquitin chains. Malt1 mutants that lack C-terminal ubiquitin acceptor lysines are impaired in rescuing NF-kappaB signaling and IL-2 production in Malt1-/- T cells. Thus, our data demonstrate that induced Malt1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing TCR signals to the canonical NF-kappaB pathway.
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PMID:Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. 1794 50

Mutations in the zinc finger of I kappa B kinase gamma (IKK gamma) are associated with hypohidrotic ectodermal dysplasia-immune deficiency (HED-ID) in which the major immune deficit is the inability to switch Ab heavy chain class. However, the pathophysiologic role of the mutations has not been fully delineated. Since help from activated Th cells is essential in Ab class switching, we sought to examine how these mutations affect T cell activation. Using a human T cell line that was null for IKK gamma, we generated cells stably expressing two of the reported mutations, namely, D406V and C417R. Cells expressing either mutation failed to induce IL-2 following stimulation with PMA/ionomycin while the induction of IL-2 was restored in cells reconstituted with the wild type IKK gamma. The lack of IL-2 upregulation correlated with the lack of NF-kappaB activation as evidenced by the inability to induce I kappa B alpha degradation, NF-kappaB binding to DNA and the expression of a reporter gene. However, both mutations did not prevent the incorporation of IKK gamma into the IKK complex and, interestingly, the induced phosphorylation of I kappa B alpha at S32 and S36 and its subsequent ubiquitination were not affected. The suppression of IL-2 induction was solely due to the inhibition of NF-kappaB activation as the mutations did not impair the activation of AP-1 and NFAT. Our data indicated that the failure of T cells to undergo activation in response to TCR stimuli may play a role in the pathophysiology of HED-ID and also showed that IKK gamma has a role in the post-ubiquitination processing of I kappa B alpha.
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PMID:Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes. 1820 44

Death-associated protein kinase (DAPK) is a unique multidomain kinase acting both as a tumor suppressor and an apoptosis inducer. The molecular mechanism underlying the effector function of DAPK is not fully understood, while the role of DAPK in T lymphocyte activation is mostly unknown. DAPK was activated after TCR stimulation. Through the expression of a dominant-negative and a constitutively active form of DAPK in T cells, we found that DAPK negatively regulated T cell activation. DAPK markedly affected T cell proliferation and IL-2 production. We identified TCR-induced NF-kappaB activation as a target of DAPK. In contrast, IL-1beta- and TNF-alpha-triggered NF-kappaB activation was not affected by DAPK. We further found that DAPK selectively modulated the TCR-induced translocation of protein kinase Ctheta, Bcl-10, and IkappaB kinase into membrane rafts. Notably, the effect of DAPK on the raft entry was specific for the NF-kappaB pathway, as other raft-associated molecules, such as linker for activation of T cells, were not affected. Our results clearly demonstrate that DAPK is a novel regulator targeted to TCR-activated NF-kappaB and T cell activation.
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PMID:The tumor suppressor death-associated protein kinase targets to TCR-stimulated NF-kappa B activation. 1829 48


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