Search results for NFKB2

Showing 21 results out of 22

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Protein (6 results from a total of 6)

Identifier: R-HSA-177674
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: NFKB2: Q00653
Identifier: R-HSA-168144
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB2: Q00653
Identifier: R-HSA-2677931
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB2: Q00653
Identifier: R-HSA-4755500
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB2: Q00653
Identifier: R-HSA-5607629
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB2: Q00653
Identifier: R-HSA-5607636
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: NFKB2: Q00653

Reaction (6 results from a total of 7)

Identifier: R-HSA-4755479
Species: Homo sapiens
Compartment: cytosol
Unprocessed NFKB2 p100 is SUMOylated with SUMO1 at lysine-90, lysine-298, lysine-689, and lysine-863 (Vatsyayan et al. 2008). SUMOylation of p100 is required for phosphorylation of p100 prior to processing to yield p52. Blockage of SUMOylation consequently interferes with import of NFKB2 p52 into the nucleus.
Identifier: R-HSA-5607723
Species: Homo sapiens
Compartment: cytosol
Phosphorylated C-terminal serines 866, 870 and 872 in NFKB2 creates binding site for beta-TRCP (beta-transducin repeat-containing protein), the receptor subunit of a SCF-type of E3 ubiquitin ligase, SCF beta-TRCP (Liang et al. 2006). The SKP1-CUL1-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation (Weathington & Mallampalli 2013). Beta-TRCP is an F-box protein that contains two domains, an F-box motif that binds SKP1 and allows assembly into SKP1-CUL1 complexes and a second protein-protein interaction domain that interacts with phosphorylated serines in NFKB2 (Bai et al. 1996, Skowyra et al. 1997, Patton et al. 1998).
Identifier: R-HSA-5607720
Species: Homo sapiens
Compartment: cytosol
NFKB2 (also known as p100) is a member of the NF-kB family of transcription factors. It is synthesised as large precursor with an N-terminal RHD (Rel homology domain) and a C-terminal series of ankyrin repeats that masks the nuclear localization signal of NFKB2/p100 localising it to the cytosol. In resting cells, p100 is associated with RELB (Transcription factor RelB) in the cytosol. Upon cell stimulation, the IkB-like C terminus of p100 is proteolyzed, resulting in RELB-p52 dimers that translocate to the nucleus (Senftleben et al. 2001, Hayden & Ghosh 2004). IKKA (I kappa-B kinase alpha) does not associate directly with p100 but in the presence of NIK (NF-kB-inducing kinase), IKKA stably binds to p100. Serine residues 866 and 870 of p100 are essential for the recruitment of IKKA to p100 by NIK. This interaction is required for p100 phosphorylation and subsequent processing by IKKA (Xiao et al. 2001, 2004).
Identifier: R-HSA-5607741
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
Following 26S-proteasomal processing, NFKB2 p52:RELB dimer is translocated from cytosol into the nucleus where it stimulates expression of target genes (Lin & Karin 2003). Dectin-1 induced RELB-p52 triggers the transcription of chemokines C-C motif chemokine 17 (CCL17) and CCL22 and repression of interleukin 12B (IL12B) transcription (Gringhuis et al. 2009).
Identifier: R-HSA-5607726
Species: Homo sapiens
Compartment: cytosol
After being recruited into the NIK (NFkB-inducing kinase) complex, activated IKKA (I kappaB kinase alpha) phosphorylates serine residues 99, 108, 115, 123, 866, 870 and 872 located in both N- and C-terminal regions of NFKB2/p100. The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100. The C-terminal serine residues create a binding site for beta-TRCP (beta-transducinrepeat-containing protein), a ubiquitin E3 ligase (Xiao et al. 2001 & 2004, Liang et al. 2006).
Identifier: R-HSA-168184
Species: Homo sapiens
Compartment: cytosol
In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kappa-B by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha (IKKa, IKK1 or CHUK) and IKK beta (IKKb, IKK2, IKBKB) associated with a regulatory subunit NEMO (IKK gamma or IKBKG). Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. In the classical or canonical NF-kappa-B pathway, the activation of the IKK complex is dependent on the phosphorylation of IKKb (IKBKB) at its activation loop and the ubiquitination of IKBKG (NEMO) (Solt et al 2009; Li et al 2002). IKKb (IKBKB) is phosphorylated at Ser177 and Ser181 (Wang et al. 2001). IKBKG (NEMO) ubiquitination by TRAF6 is required for optimal activation of the IKK kinase activity; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination. Activated IKK complex phosphorylates IkB alpha (IkBa or NFKBIA) on Ser32 and Ser36 leading to K48-linked ubiquitination and proteasome-dependent degradation of IkB alpha. This leads to the release of active NF-kappa-B dimers.

This Reactome event shows phosphorylation of IKK beta (IKBKB) by TGF-β–activated kinase 1 (TAK1), encoded by the MAP3K7 gene. TAK1 functions downstream of receptor signaling complexes in TLR, TNF-alpha and IL-1 signaling pathways (Xu & Lei 2021). TAK1 appears to be essential for IL-1-induced NF-kappa-B activation since a specific TAK1 inhibitor (5Z)-7-oxozeaenol prevents NF-kappa-B activation in human umbilical vein endothelial cells (HUVEC) (Lammel 2020); also, it prevents NF-kappa-B-mediated TNF production in human myeloid leukaemia U937 cells (Rawlins et al. 1999). TAK1 functions through assembling the TAK1 complex consisting of the coactivators TAB1 and either TAB2 or TAB3 (Shibuya et al. 1996, Sakurai et al. 2000; Xu & Lei 2021). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe (Sakurai et al. 2000; Brown et al. 2005). The TAK1 complex is regulated by polyubiquitination. The binding of TAB2 or TAB3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2, -3 by TRAF6 (Ishitani et al. 2003), which in turn results in conformational changes within the TAK1 complex. TAB2 or -3 is recruited to K63-linked polyubiquitin chains of receptor interacting protein (RIP) kinase RIP1 (RIPK1) via the Zinc finger domain of TAB2 or TAB3. RIPK1 functions as an essential component of inflammatory and immune signaling pathways. Ubiquitination of RIPK1 follows the recruitment of TRADD and TRAF2 or -5 (the latter functions as the E3 ubiquitin ligase, but also cIAP1,-2 can ubiquitinate RIPK1 as a response to TNF receptor engagement (Varfolomeev et al. 2008). The IKK complex is also recruited ubiquitin (Ub) chains via its Ub binding domain. Polyubiquitin chains may function as a scaffold for higher order signaling complexes bringing the TAK1 and IKK complexes in close proximity and allowing TAK1 to phosphorylate IKBKB (IKK2) (Kanayama et al. 2004).

The alternative (non-canonical) pathway can be activated via CD40, LTßR, BAFF, RANK, and is therefore limited to cells which express these receptors. It leads to NIK-mediated phosphorylation of IKKa (IKK1, CHUK), which phosphorylates the NFKB2 (p52) precursor p100, leading to the ubiquitin-dependent degradation of its C-terminal part (processing of p100 to the mature p52 subunit) and releasing the NFKB2:RelB complex (Sun 2017). In non-stimulated cells NIK is constitutively degraded by the cIAP1/2:TRAF2:TRAF3 Ub ligase complex; following stimulation, the complex is recruited to the respective receptor comlex where cIAPs ubiquitinates TRAF3, resulting it its degradation and stabilization of NIK. NIK then phosphorylates and activates IKK1 (CHUK), leading to the NFKB2:RelB complex activation (Sun 2017). TRAF3 deubiquitylation by OTUD7B downregulates the NIK-mediated NF-kappa-B activation. (Hu et al 2013). In addition, TAK1 has been shown to interact with NIK and with IKK2, and TAK1 can be stimulated by anti-apoptotic protein, XIAP (Hofer-Warbinek et al. 2000). XIAP is an NF-kB dependent gene, therefore its expression represents a positive regulatory circuit. NIK is also involved in the classical pathway, and is activated by TAK1 in the IL-1 signalling pathway (Ninomiya-Tsui et al. 1999) and Hemophilus influenzae-induced TLR2 signalling pathway (Shuto et al. 2001).

RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid (N) protein serves as a platform to enhance the interaction between TAK1 and IKK complexes promoting NF-kappa-B-dependent inflammatory responses (Wu Y et al. 2021).

Set (2 results from a total of 2)

Identifier: R-HSA-177656
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-177662
Species: Homo sapiens
Compartment: nucleoplasm

Complex (3 results from a total of 3)

Identifier: R-HSA-177673
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-168155
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5607703
Species: Homo sapiens
Compartment: cytosol

Pathway (4 results from a total of 4)

Identifier: R-HSA-4755510
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
NF-kappaB transcription factors are sequestered in the cytosol due to their association with IkappaB. During activation of NF-kappaB, IKK phosphorylates IkappaB, releasing NF-kappaB for importation into the nucleus. NF-kappaB transcription factors, the NFKBIA component of IkappaB, and subunits of the IKK complex can be SUMOylated (reviewed in Kracklauer and Schmidt 2003, Liu et al. 2013). SUMOylations of IkappaB, NFKBIA, and RELA inhibit NF-kappaB signaling; SUMOylation of NFKB2 is required for proteolytic processing.
Identifier: R-HSA-5607761
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
In addition to the activation of canonical NF-kB subunits, activation of SYK pathway by Dectin-1 leads to the induction of the non-canonical NF-kB pathway, which mediates the nuclear translocation of RELB-p52 dimers through the successive activation of NF-kB-inducing kinase (NIK) and IkB kinase-alpha (IKKa) (Geijtenbeek & Gringhuis 2009, Gringhuis et al. 2009). Noncanonical activity tends to build more slowly and remain sustained several hours longer than does the activation of canonical NF-kB. The noncanonical NF-kB pathway is characterized by the post-translational processing of NFKB2 (Nuclear factor NF-kappa-B) p100 subunit to the mature p52 subunit. This subsequently leads to nuclear translocation of p52:RELB (Transcription factor RelB) complexes to induce cytokine expression of some genes (C-C motif chemokine 17 (CCL17) and CCL22) and transcriptional repression of others (IL12B) (Gringhuis et al. 2009, Geijtenbeek & Gringhuis 2009, Plato et al. 2013).
Identifier: R-HSA-5676590
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
In addition to the activation of canonical NF-kB subunits, activation of SYK pathway by Dectin-1 leads to the induction of the non-canonical NF-kB pathway, which mediates the nuclear translocation of RELB-p52 dimers through the successive activation of NF-kB-inducing kinase (NIK) and IkB kinase-alpha (IKKa) (Geijtenbeek & Gringhuis 2009, Gringhuis et al. 2009). Noncanonical activity tends to build more slowly and remain sustained several hours longer than does the activation of canonical NF-kB. The noncanonical NF-kB pathway is characterized by the post-translational processing of NFKB2 (Nuclear factor NF-kappa-B) p100 subunit to the mature p52 subunit. This subsequently leads to nuclear translocation of p52:RELB (Transcription factor RelB) complexes to induce cytokine expression of some genes (C-C motif chemokine 17 (CCL17) and CCL22) and transcriptional repression of others (IL12B) (Gringhuis et al. 2009, Geijtenbeek & Gringhuis 2009, Plato et al. 2013).
Identifier: R-HSA-5668541
Species: Homo sapiens
Compartment: plasma membrane, nucleoplasm
Tumor necrosis factor-alpha (TNFA) exerts a wide range of biological effects through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Under normal physiological conditions TNFR2 exhibits more restricted expression, being found on certain subpopulation of immune cells and few other cell types (Grell et al. 1995 ). TNFR1 mediated signalling pathways have been very well characterized but, TNFR2 has been much less well studied. TNFR1 upon activation by TNFA activates apoptosis through two pathways, involving the adaptor proteins TNFR1-associated death domain (TRADD) and fas-associated death domain (FADD). In contrast, TNFR2 signalling especially in highly activated T cells, induces cell survival pathways that can result in cell proliferation by activating transcription factor NF-kB (nuclear factor-kB) via the alternative non-canonical route. TNFR2 signalling seems to play an important role, in particular for the function of regulatory T cells. It offers protective roles in several disorders, including autoimmune diseases, heart diseases, demyelinating and neurodegenerative disorders and infectious diseases (Faustman & Davis 2010).
Activation of the non-canonical pathway by TNFR2 is mediated through a signalling complex that includes TNF receptor-associated factor (TRAF2 and TRAF3), cellular inhibitor of apoptosis (cIAP1 and cIAP2), and NF-kB-inducing kinase (NIK). In this complex TRAF3 functions as a bridging factor between the cIAP1/2:TRAF2 complex and NIK. In resting cells cIAP1/2 in the signalling complex mediates K48-linked polyubiquitination of NIK and subsequent proteasomal degradation making NIK levels invisible. Upon TNFR2 stimulation, TRAF2 is recruited to the intracellular TRAF binding motif and this also indirectly recruits TRAF1 and cIAP1/2, as well as TRAF3 and NIK which are already bound to TRAF2 in unstimulated cells. TRAF2 mediates K63-linked ubiquitination of cIAP1/2 and this in turn mediates cIAP dependent K48-linked ubiquitination of TRAF3 leading to the proteasome-dependent degradation of the latter. As TRAF3 is degraded, NIK can no longer interact with TRAF1/2:cIAP complex. As a result NIK concentration in the cytosol increases and NIK gets stabilised and activated. Activated NIK phosphorylates IKKalpha, which in turn phosphorylates p100 (NFkB2) subunit. Phosphorylated p100 is also ubiquitinated by the SCF-beta-TRCP ubiquitin ligase complex and is subsequently processed by the proteaseome to p52, which is a transcriptionally competent NF-kB subunit in conjunction with RelB (Petrus et al. 2011, Sun 2011, Vallabhapurapu & Karin 2009).
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