TAK1 activates NF-kB by phosphorylation and activation of IKK complex (Homo sapiens)

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3, 55-78, 101, 2, 109cytosolnucleoplasmIKBKG NFKBIA NFKB2(1-454) RELA ADPADPNFKBIB NFkB ComplexAPP(672-713) RELA NFKB1(1-433) NFKB1(1-433) APP(672-711) p-S176,S180-IKKA NECML Phospho-NF-kappaBInhibitorMYD88 IKKA:IKBKB:IKBKGPeptide ATPSAA1(19-122) IKBKGNFkB ComplexS100A12 Activated IKKComplexAGER ligands:AGERIkBs:NFkBIKKAIKKA ATPDHX9:CpG:MyD88HMGB1 S100B NFKB2(1-454) IKBKG NFKB1(1-433) IKBKBp-S177,S181-IKBKB N-epsilon-(1-(1-carboxy)ethyl)lysine RELA IKBKB AGER Activated TAKcomplexesDHX9 NFKB2(1-454) 4


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. Source:Reactome.

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Bibliography

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  1. Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed Europe PMC Scholia
  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 Europe PMC Scholia
  3. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
  4. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed Europe PMC Scholia
  5. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia
  6. 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 Europe PMC Scholia
  7. 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 Europe PMC Scholia
  8. 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 Europe PMC Scholia
  9. Chen ZJ.; ''Ubiquitin signalling in the NF-kappaB pathway.''; PubMed Europe PMC Scholia
  10. Yazdi S, Naumann M, Stein M.; ''Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB.''; PubMed Europe PMC Scholia
  11. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
  12. Jacobs MD, Harrison SC.; ''Structure of an IkappaBalpha/NF-kappaB complex.''; PubMed Europe PMC Scholia
  13. 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 Europe PMC Scholia
  14. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC Scholia
  15. 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 Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
117964view10:54, 23 May 2021EweitzModified title
117957view10:52, 23 May 2021EweitzModified title
114679view16:15, 25 January 2021ReactomeTeamReactome version 75
113126view11:19, 2 November 2020ReactomeTeamReactome version 74
112358view15:28, 9 October 2020ReactomeTeamReactome version 73
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)
Activated TAK complexesR-HSA-772536 (Reactome)
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)
IKKA ProteinO15111 (Uniprot-TrEMBL)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
IKKAProteinO15111 (Uniprot-TrEMBL)
IkBs:NFkBComplexR-HSA-168130 (Reactome)
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)
Peptide MetaboliteCHEBI:16670 (ChEBI)
Phospho-NF-kappaB InhibitorR-HSA-177678 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
S100A12 ProteinP80511 (Uniprot-TrEMBL)
S100B ProteinP04271 (Uniprot-TrEMBL)
SAA1(19-122) ProteinP0DJI8 (Uniprot-TrEMBL)
p-S176,S180-IKKA ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (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)
DHX9:CpG:MyD88ArrowR-HSA-168166 (Reactome)
IKBKBR-HSA-5609665 (Reactome)
IKBKGR-HSA-5609665 (Reactome)
IKKA:IKBKB:IKBKGArrowR-HSA-5609665 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-168184 (Reactome)
IKKAR-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 IKK complexes that range from 700 to 900 kDa have been isolated and characterized (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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