Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IkappaB kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-kappaB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKbeta, but not IKKalpha, is required for Tpl2 activation. Moreover, this novel function of IKKbeta appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-kappaB1/p105. These findings suggest that IKKbeta exerts its immune-regulatory functions by targeting different downstream signaling pathways.
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PMID:IkappaB kinase is an essential component of the Tpl2 signaling pathway. 1519 57

Two members of the NF-kappaB (nuclear factor kappaB)/Rel transcription factor family, NF-kappaB1 and NF-kappaB2, are produced as precursor proteins, NF-kappaB1 p105 and NF-kappaB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-kappaB1 p50 and NF-kappaB2 p52. p105 and p100 are known to function additionally as IkappaBs (inhibitors of NF-kappaB), which retain associated NF-kappaB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-kappaB1 and NF-kappaB2 in immune cells. NF-kappaB2 p100 processing has recently been shown to be stimulated by a subset of NF-kappaB inducers, including lymphotoxin-beta, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-kappaB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-kappaB1 has a distinct function from NF-kappaB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-alpha and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-kappaB activation, p105 functions as a regulator of MAP kinase signalling.
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PMID:Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology. 1521 41

The MEK kinase TPL-2 (also known as Cot) is required for lipopolysaccharide (LPS) activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase cascade in macrophages and consequent upregulation of genes involved in innate immune responses. In resting cells, TPL-2 forms a stoichiometric complex with NF-kappaB1 p105, which negatively regulates its MEK kinase activity. Here, it is shown that lipopolysaccharide (LPS) stimulation of primary macrophages causes the release of both long and short forms of TPL-2 from p105 and that TPL-2 MEK kinase activity is restricted to this p105-free pool. Activation of TPL-2, MEK, and ERK by LPS is also demonstrated to require proteasome-mediated proteolysis. p105 is known to be proteolysed by the proteasome following stimulus-induced phosphorylation of two serines in its PEST region by the IkappaB kinase (IKK) complex. Expression of a p105 point mutant, which is not susceptible to signal-induced proteolysis, in RAW264.7 macrophages impairs LPS-induced release of TPL-2 from p105 and its subsequent activation of MEK. Furthermore, expression of wild-type but not mutant p105 reconstitutes LPS stimulation of MEK and ERK phosphorylation in primary NF-kappaB1-deficient macrophages. Consistently, pharmacological blockade of IKK inhibits LPS-induced release of TPL-2 from p105 and TPL-2 activation. These data show that IKK-induced p105 proteolysis is essential for LPS activation of TPL-2, thus revealing a novel function of IKK in the regulation of the ERK MAP kinase cascade.
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PMID:Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. 1548 31

This study investigated for the first time the effects of the cis isomer of RESV (c-RESV), a polyphenol present in red wine, on an array of genes whose expression is controlled by nuclear factor kappa B (NF-kappaB) and whose transcriptional activation is critical in a number of pathologies (including some cardiovascular diseases). In inflammatory peritoneal macrophages stimulated with lipopolysaccharide (LPS) and gamma interferon (IFN-gamma), c-RESV significantly blocked the expression of genes related to the REL/NF-kappaB/IkappaB family, adhesion molecules and acute-phase proteins; however, the greatest modulatory effect was obtained on the expression of genes related to the pro-inflammatory cytokines. c-RESV down-regulated the nuclear factor of kappa light chain gene enhancer in B-cells 1 (NFkappaBL1) gene product p105 and up-regulated the nuclear factor of kappa light chain gene enhancer in B-cells inhibitor alpha (IkappaBalpha) gene. c-RESV also significantly inhibited intercellular adhesion molecule-1 (ICAM-1) gene expression and the transmembrane receptors RIP (receptor TNFRSF) and TLR3 (toll-like receptor 7). At 100 muM, c-RESV significantly inhibited transcription of Scya2 (chemokine MCP-1), the chemokine RANTES (regulated on activation, normal T cell expressed and secreted), pro-inflammatory cytokines that attract monocyte-granulocyte cells such as M-CSF (colony-stimulating factor 1), GM-CSF (colony-stimulating factor 2) and G-CSF (colony-stimulating factor 3), the cytokine tumor growth factor beta (TGF-beta) and the extracellular ligand IL-1alpha. In contrast, c-RESV stimulated transcription of the pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha (TNF-alpha), the extracellular ligand IL-1beta, and the IFN regulatory factor (IRF)-1. In conclusion, c-RESV has a significant modulatory effect on the NF-kappaB signaling pathway and, consequently, an important antioxidant role that may partially explain the cardioprotective effects attributed to long-term moderate red wine consumption.
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PMID:Effect of cis-resveratrol on genes involved in nuclear factor kappa B signaling. 1565 68

The serine-threonine protein kinase encoded by the Tpl2 protooncogene transduces Toll-like and death receptor signals in a variety of cell types and plays an important role in innate immunity and inflammation. Differential translational initiation of the Tpl2 mRNA gives rise to 58-kDa (p58) and 52-kDa (p52) isoforms. In unstimulated cells, both isoforms are stabilized and inactivated by stoichiometric binding to NF-kappaB1/p105. After lipopolysaccharide or TNF-alpha stimulation, p58 is released from p105 preferentially relative to p52. The released p58 is active but unstable and undergoes rapid degradation via the proteasome. Recent studies revealed that Tpl2 undergoes phosphorylation at Thr-290 and that phosphorylation at this site is required for activation. Here, we present evidence showing that it is the p58 isoform that is preferentially phosphorylated at Thr-290 and that phosphorylation is more efficient when p58 is complexed to p52. Because p58 is preferentially released from p105 after stimulation, we examined whether Tpl2 phosphorylation at this site controls the dissociation of the two proteins in response to external signals and the subsequent events leading to the activation of Tpl2. The results showed that lipopolysaccharide-induced Tpl2 phosphorylation at Thr-290 in macrophages promotes the release of Tpl2 from p105, contributes to the enzymatic activation of the Tpl2 kinase, and is required for the degradation of Tpl2 via the proteasome.
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PMID:Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. 1569 25

Laxifolone A is a triterpene isolated from Euonymus laxiflorus Champ. Exposure of RAW264.7 macrophages to laxifolone A concentration-dependently suppressed lipopolysaccharide/interferon-gamma (LPS/IFN-gamma)-induced nitrite production (IC50 = 0.37 +/- 0.05 microM), inducible NO synthase (iNOS) protein, and iNOS mRNA expression. Translocation of nuclear factor-kappaB (NF-kappaB) into the nucleus with subsequent activation of iNOS gene transcription is essential in NO signaling. Western blot analysis indicated that the cytosolic NF-kappaB/p65 was obviously decreased after LPS/IFN-gamma stimulation for 30 min and this phenomenon could be reversed by laxifolone A. Similarly, a time-related NF-kappaB/p65 nuclear translocation induced by LPS/IFN-gamma was diminished in the presence of laxifolone A. However, laxifolone A failed to interfere in LPS/IFN-gamma-evoked IkappaB degradation. Our results also showed that LPS/IFN-gamma-stimulation resulted in the degradation of NF-kappaB p105, the NF-kappaB precursor, and laxifolone A treatment significantly counteracted this effect. Furthermore, laxifolone A itself was able to enhance NF-kappaB p105 protein expression. In summary, these results suggest that inhibition of NF-kappaB p105 degradation in cytoplasm may participate in the abrogation of LPS/IFN-gamma-induced NF-kappaB translocation and subsequent NO synthesis by laxifolone A.
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PMID:Laxifolone A suppresses LPS/IFN-gamma-induced NO synthesis by attenuating NF-kappaB translocation: role of NF-kappaB p105 level. 1597 Nov 21

Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both COT 30--467 and COT 30--397 are expressed in a soluble and stable form when produced in complex with the C-terminal half of p105. The k(cat) of COT 30--397 is reduced approximately 47--fold in the COT 30--467/p105 Delta N complex. COT prefers Mn(2+) to Mg(2+) as the ATP metal cofactor, exhibiting an unusually high ATP K(m) in the presence of Mg(2+). When using Mn(2+) as the cofactor, the ATP K(m) is reduced to a level typical of most kinases. In contrast, the binding affinity of COT for its other substrate MEK is cofactor independent. Our results using purified proteins indicate that p105 binding improves COT solubility and stability while down-regulating kinase activity, consistent with cellular data showing that p105 functions as an inhibitor of COT.
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PMID:Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-kappa B1 p105. 1608 50

The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS). In response to LPS stimulation, Tpl2 phosphorylates a downstream kinase, MEK1, leading to the activation of ERK signaling pathway. Recent studies demonstrate that the NF-kappaB1 precursor protein p105 functions as an inhibitor of Tpl2 and that the LPS-stimulated Tpl2 activation requires p105 degradation. However, how p105 inhibits the signaling function of Tpl2 is not completely understood. We show here that p105 does not inhibit the intrinsic kinase activity of Tpl2. When complexed with p105, Tpl2 remains catalytically active and uses p105 as a substrate. However, the p105-bound Tpl2 is unable to phosphorylate its physiological target, MEK1. These findings suggest that p105 functions as a competitive inhibitor of Tpl2 that blocks its access by MEK1.
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PMID:Phosphorylation of NF-kappaB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation. 1644 10

The protein kinase COT/Tpl2 is activated by interleukin-1 (IL-1), TNFalpha and lipopolysaccharide, and its activation by these agonists involves the IkappaB kinase beta (IKKbeta) catalysed phosphorylation of the p105 regulatory subunit. Here, we show that COT activation also requires catalytic subunit phosphorylation, since IL-1beta induced a 5-10-fold activation of a COT mutant unable to bind p105. Activation was paralleled by the phosphorylation of Thr290 and Ser62 and unaffected by the IKKbeta inhibitor PS1145 at concentrations which prevented the degradation of IkappaBalpha. Mutagenesis experiments indicated that COT activation is initiated by Thr290 phosphorylation catalysed by an IL-1-stimulated protein kinase distinct from IKKbeta, while Ser62 phosphorylation is an autophosphorylation event required for maximal activation.
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PMID:Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62. 1680 91

Toll-like receptors (TLRs) are a recently described receptor class involved in the regulation of innate and adaptive immunity. Here, we demonstrate that arrestin-2 and GRK5 (G protein-coupled receptor kinase 5), proteins that regulate G protein-coupled receptor signaling, play a negative role in TLR4 signaling in Raw264.7 macrophages. We find that lipopolysaccharide (LPS)-induced ERK1/2 phosphorylation is significantly enhanced in arrestin-2 and GRK5 knockdown cells. To elucidate the mechanisms involved, we tested the effect of arrestin-2 and GRK5 knockdown on LPS-stimulated signaling components that are upstream of ERK phosphorylation. Upon LPS stimulation, IkappaB kinase promotes phosphorylation and degradation of NFkappaB1 p105 (p105), which releases TPL2 (a MAP3K), which phosphorylates MEK1/2, which in turn phosphorylates ERK1/2. We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation. GRK5 knockdown also results in enhanced IkappaB kinase-mediated p105 phosphorylation and degradation, whereas GRK2 and GRK6 knockdown have no effect on this pathway. In vitro analysis demonstrates that arrestin-2 directly binds to the COOH-terminal domain of p105, whereas GRK5 binds to and phosphorylates p105. Taken together, these results suggest that p105 phosphorylation by GRK5 and binding of arrestin-2 negatively regulates LPS-stimulated ERK activation. These results reveal that arrestin-2 and GRK5 are important negative regulatory components in TLR4 signaling.
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PMID:Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. 1698 Mar 1


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