Search results for NFKB1

Showing 19 results out of 35

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Species

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Interactor (3 results from a total of 3)

Identifier: P19838-1
Species: Homo sapiens
Primary external reference: UniProt: P19838-1
Identifier: P19838-PRO_0000030311
Species: Homo sapiens
Primary external reference: UniProt: P19838-PRO_0000030311
Identifier: P19838-2
Species: Homo sapiens
Primary external reference: UniProt: P19838-2

Protein (5 results from a total of 8)

Identifier: R-HSA-177655
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: NFKB1: P19838
Identifier: R-HSA-168168
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB1: P19838
Identifier: R-HSA-6801004
Species: Homo sapiens
Compartment: secretory granule lumen
Primary external reference: UniProt: NFKB1: P19838
Identifier: R-HSA-6799557
Species: Homo sapiens
Compartment: specific granule lumen
Primary external reference: UniProt: NFKB1: P19838
Identifier: R-HSA-451619
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB1: P19838

Complex (5 results from a total of 18)

Identifier: R-HSA-451638
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5684265
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5687880
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-194043
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-194047
Species: Homo sapiens
Compartment: nucleoplasm

Set (1 results from a total of 1)

Identifier: R-HSA-177656
Species: Homo sapiens
Compartment: cytosol

Reaction (4 results from a total of 4)

Identifier: R-HSA-2730894
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
Identifier: R-HSA-209063
Species: Homo sapiens
Compartment: cytosol
SCF (Beta-TrCP) ubiquitinates phosphorylated I kappa B alpha.
Identifier: R-HSA-451634
Species: Homo sapiens
Compartment: cytosol
The C-terminal half of NFKB1 p105 forms a high-affinity stoichiometric association with MAP3K8 (TPL2) via two distinct interactions (Belich et al. 1999; Beinke et al. 2003). The Tpl2 C-terminus (residues 398-467) binds to a region N-terminal to the p105 ankyrin repeat region (human p105 residues 497-534), whereas the Tpl2 kinase domain interacts with the p105 death domain (Beinke et al. 2003). In unstimulated macrophages, all detectable Tpl2 is associated with p105 (Belich et al. 1999; Lang et al. 2004). Binding to p105 maintains the stability of Tpl2 but inhibits Tpl2 MEK kinase activity by preventing access to MEK (Beinke et al. 2003; Waterfield et al. 2003). Tpl2 phosphorylation at Thr-290 may also play a role in the activation of Tpl2 (Cho & Tsichlis 2005).

A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.
Identifier: R-HSA-5692315
Species: Homo sapiens
Compartment: plasma membrane
T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 (also known as TNFRSF4 or CD134) plays a key role in the survival and homeostasis of effector and memory T cells (Godfrey et al. 1994, Kashiwakura et al. 2004, Zingoni et al. 2004). OX40 mediates this costimulation by binding to its partner OX40L (also known as TNFSF4 or CD252). OX40 is a type I transmembrane protein expressed predominantly on T-lymphocytes early after antigen activation. It binds with OX40L trimer expressed on activated antigen presenting cells and endothelial cells within acute inflammatory environments. OX40 mediates signalling independently and also can augment antigen-driven TCR signalling. OX40 signalling leads to the activation of NFkB1 (p50-RELA) to stimulate survival signals to T cells in the absence of antigen recognition. It can also activate hence to activation of noncanonical NF-κB2 (p52-RELB) through NIK which might also be necessary for transmitting survival signals (Kawamata et al. 1998, Arch et al. 1998). OX40 can also enhance TCR-induced calcium influx, leading to strong nuclear accumulation of NFATc1 and NFATc2 that likely regulate production of cytokines (So et al. 2006, Croft 2010).

Pathway (1 results from a total of 1)

Identifier: R-HSA-5684264
Species: Homo sapiens
Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).

In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.

MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).

MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).

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