TAK1 activates NFkB by phosphorylation and activation of IKKs complex (Homo sapiens)

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6, 9112, 133, 6, 1012-14cytosolnucleoplasmDHX9:CpG:MyD88IKBKGTAB3 IKBKBNFKBIA RELA Activated TAKcomplexesUBE2N NFKB2(1-454) ADPK63polyUb K63polyUb-TRAF6 TAB1 ATPUBE2V1 S100B IkBs:NFkBPeptide IKBKG TAB2 IKBKB p-S32,S36-NFKBIA MAP3K7 DHX9 RELA APP(672-711) MDP SAA1(19-122) NFKB1(1-433) NOD2 ATPp-2S,S376,T,T209,T387-IRAK1 NFKB1(1-433) MYD88 IKBKG APP(672-713) NFkB ComplexAGER NFKBIB NFKB2(1-454) iE-DAP AGER ligands:AGERp-S177,S181-IKBKB N-epsilon-(1-(1-carboxy)ethyl)lysine Unmethylated CpG DNA p-S176,S180-IKKA S100A12 NFKB2(1-454) NFKB1(1-433) HMGB1 Phospho-NF-kappaBInhibitorp-IRAK2 CHUK:IKBKB:IKBKGNFkB ComplexNECML NOD1 Activated IKKComplexCHUK Ub-209-RIPK2 ADPCHUKp-S19,S23-NFKBIB p-T184,T187-MAP3K7 IKBKG RELA 754, 81, 4, 8


Description

NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 445989
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Shamovsky, Veronica

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Ontology Terms

 

Bibliography

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  1. Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A.; ''Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site.''; PubMed
  2. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, Dittrich-Breiholz O, Graue N, Dörrie A, Schneider H, Wirth D, Luckow B, Resch K, Kracht M.; ''Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes.''; PubMed
  3. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed
  4. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed
  5. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed
  6. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed
  7. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed
  8. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed
  9. Gil J, Alcamí J, Esteban M.; ''Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.''; PubMed
  10. Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed
  11. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed
  12. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed
  13. Chen ZJ.; ''Ubiquitin signalling in the NF-kappaB pathway.''; PubMed

History

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CompareRevisionActionTimeUserComment
101260view11:15, 1 November 2018ReactomeTeamreactome version 66
100798view20:43, 31 October 2018ReactomeTeamreactome version 65
100340view19:20, 31 October 2018ReactomeTeamreactome version 64
99885view16:03, 31 October 2018ReactomeTeamreactome version 63
99442view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94029view13:52, 16 August 2017ReactomeTeamreactome version 61
93651view11:29, 9 August 2017ReactomeTeamreactome version 61
88410view11:47, 5 August 2016FehrhartOntology Term : 'nuclear factor kappa B signaling pathway' added !
86768view09:25, 11 July 2016ReactomeTeamreactome version 56
83056view09:47, 18 November 2015ReactomeTeamVersion54
81363view12:53, 21 August 2015ReactomeTeamVersion53
76831view08:05, 17 July 2014ReactomeTeamFixed remaining interactions
76535view11:51, 16 July 2014ReactomeTeamFixed remaining interactions
75868view09:51, 11 June 2014ReactomeTeamRe-fixing comment source
75568view10:37, 10 June 2014ReactomeTeamReactome 48 Update
74923view13:45, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74567view08:36, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AGER ProteinQ15109 (Uniprot-TrEMBL)
AGER ligands:AGERComplexR-HSA-879365 (Reactome)
APP(672-711) ProteinP05067 (Uniprot-TrEMBL)
APP(672-713) ProteinP05067 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexR-HSA-177663 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
Activated TAK complexesComplexR-HSA-772536 (Reactome)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CHUKProteinO15111 (Uniprot-TrEMBL)
DHX9 ProteinQ08211 (Uniprot-TrEMBL)
DHX9:CpG:MyD88ComplexR-HSA-3134868 (Reactome)
HMGB1 ProteinP09429 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKBProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKGProteinQ9Y6K9 (Uniprot-TrEMBL)
IkBs:NFkBComplexR-HSA-168130 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MDP MetaboliteCHEBI:59414 (ChEBI)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
N-epsilon-(1-(1-carboxy)ethyl)lysine MetaboliteCHEBI:60125 (ChEBI)
NECML MetaboliteCHEBI:53014 (ChEBI)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB2(1-454) ProteinQ00653 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
NFkB ComplexComplexR-HSA-168155 (Reactome)
NFkB ComplexComplexR-HSA-177673 (Reactome)
NOD1 ProteinQ9Y239 (Uniprot-TrEMBL)
NOD2 ProteinQ9HC29 (Uniprot-TrEMBL)
Peptide MetaboliteCHEBI:16670 (ChEBI)
Phospho-NF-kappaB InhibitorComplexR-HSA-177678 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
S100A12 ProteinP80511 (Uniprot-TrEMBL)
S100B ProteinP04271 (Uniprot-TrEMBL)
SAA1(19-122) ProteinP0DJI8 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-209-RIPK2 ProteinO43353 (Uniprot-TrEMBL)
Unmethylated CpG DNA R-NUL-3134861 (Reactome)
iE-DAP MetaboliteCHEBI:59271 (ChEBI)
p-2S,S376,T,T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL) This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-S176,S180-IKKA ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S19,S23-NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-168140 (Reactome)
ADPArrowR-HSA-168184 (Reactome)
AGER ligands:AGERArrowR-HSA-168166 (Reactome)
ATPR-HSA-168140 (Reactome)
ATPR-HSA-168184 (Reactome)
Activated IKK ComplexArrowR-HSA-168184 (Reactome)
Activated IKK Complexmim-catalysisR-HSA-168140 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-168184 (Reactome)
CHUK:IKBKB:IKBKGArrowR-HSA-5609665 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-168184 (Reactome)
CHUKR-HSA-5609665 (Reactome)
DHX9:CpG:MyD88ArrowR-HSA-168166 (Reactome)
IKBKBR-HSA-5609665 (Reactome)
IKBKGR-HSA-5609665 (Reactome)
IkBs:NFkBR-HSA-168140 (Reactome)
NFkB ComplexArrowR-HSA-168140 (Reactome)
NFkB ComplexArrowR-HSA-168166 (Reactome)
NFkB ComplexR-HSA-168166 (Reactome)
Phospho-NF-kappaB InhibitorArrowR-HSA-168140 (Reactome)
R-HSA-168140 (Reactome) In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits.

A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.

R-HSA-168166 (Reactome) NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.
R-HSA-168184 (Reactome) In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.

This basic trimolecular complex is referred to as the IKK complex. 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.

IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

R-HSA-5609665 (Reactome) The multimeric I kappa B kinase (IKK) complex is a key regulator of NFkB signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKA (IKBKA) and IKKB (IKBKB) kinases, and a regulatory subunit, NFkB essential modulator (IKBKG/NEMO/IKKG). IKBKG (NEMO) associates with the unphosphorylated IKK kinase C-termini and activates the IKK complex’s catalytic activity (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008).
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