Target Information
Target General Infomation | |||||
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Target ID |
T32335
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Former ID |
TTDC00222
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Target Name |
Inhibitor of nuclear factor kappa-B kinase
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Gene Name |
IKBKE
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Synonyms |
I kappa B kinase; IKK; IkBK; IKBKE
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Target Type |
Research
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Disease | Arthritis [ICD9: 710-719; ICD10: M00-M25] | ||||
Multiple myeloma [ICD9: 203; ICD10: C90] | |||||
Function |
Serine kinase that plays an essential role in the NF- kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators sincethey exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.
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BioChemical Class |
Kinase
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Target Validation |
T32335
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UniProt ID | |||||
EC Number |
EC 2.7.11.10
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Sequence |
MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLR
KLNHQNIVKLFAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVV AGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYL HPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTE KPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPILANILEVEQAKCWGFDQFFA ETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQEYLFEGHLCV LEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLG AGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSV AGTPEIQELKAAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSI QQIQCCLDKMNFIYKQFKKSRMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKY QASLVTHGKRMRVVHETRNHLRLVGCSVAACNTEAQGVQESLSKLLEELSHQLLQDRAKG AQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDNNRIIERLNRVPAPPDV |
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Structure |
3BRT; 3BRV; 4E3C; 4KIK
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Inhibitor | 4-hydroxy-2-nonenal | Drug Info | [535178] | ||
5-Bromo-6-methoxy-9H-beta-carboline | Drug Info | [526654] | |||
Arsenite | Drug Info | [535043] | |||
BMS-345541 | Drug Info | [535797] | |||
compound 17d | Drug Info | [532095] | |||
MLN-120B | Drug Info | [528076] | |||
MRT67307 | Drug Info | [531284] | |||
PS-1145 | Drug Info | [537114] | |||
S1627 | Drug Info | [535912] | |||
TPCA-1 | Drug Info | [527173] | |||
Pathways | |||||
PathWhiz Pathway | Intracellular Signalling Through Adenosine Receptor A2a and Adenosine | ||||
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine | |||||
Reactome | Activation of NF-kappaB in B cells | ||||
NOD1/2 Signaling Pathway | |||||
RIP-mediated NFkB activation via ZBP1 | |||||
AKT phosphorylates targets in the cytosol | |||||
p75NTR recruits signalling complexes | |||||
NF-kB is activated and signals survival | |||||
FCERI mediated NF-kB activation | |||||
Interleukin-1 signaling | |||||
Regulation of TNFR1 signaling | |||||
TNFR1-induced NFkappaB signaling pathway | |||||
IKBKB deficiency causes SCID | |||||
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) | |||||
IkBA variant leads to EDA-ID | |||||
Dectin-1 mediated noncanonical NF-kB signaling | |||||
CLEC7A (Dectin-1) signaling | |||||
Constitutive Signaling by AKT1 E17K in Cancer | |||||
NIK--> | |||||
noncanonical NF-kB signaling | |||||
MAP3K8 (TPL2)-dependent MAPK1/3 activation | |||||
TRAF6 mediated IRF7 activation | |||||
TRAF6 mediated NF-kB activation | |||||
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 | |||||
Negative regulators of RIG-I/MDA5 signaling | |||||
Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon | |||||
IRAK1 recruits IKK complex | |||||
IKK complex recruitment mediated by RIP1 | |||||
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation | |||||
WikiPathways | Toll-like receptor signaling pathway | ||||
Estrogen signaling pathway | |||||
TCR Signaling Pathway | |||||
Insulin Signaling | |||||
IL-4 Signaling Pathway | |||||
MAPK Signaling Pathway | |||||
NLR Proteins | |||||
Induction (Part 1 of 3) | |||||
MyD88 cascade initiated on plasma membrane | |||||
Cardiac Hypertrophic Response | |||||
Cytosolic sensors of pathogen-associated DNA | |||||
MyD88 dependent cascade initiated on endosome | |||||
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways | |||||
Mal cascade initiated on plasma membrane | |||||
Fc epsilon receptor (FCERI) signaling | |||||
MyD88-independent cascade | |||||
Signaling by the B Cell Receptor (BCR) | |||||
TAK1 activates NFkB by phosphorylation and activation of IKKs complex | |||||
Structural Pathway of Interleukin 1 (IL-1) | |||||
EBV LMP1 signaling | |||||
Polycystic Kidney Disease Pathway | |||||
Apoptosis | |||||
Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis | |||||
BDNF signaling pathway | |||||
Interleukin-11 Signaling Pathway | |||||
AGE/RAGE pathway | |||||
TNF alpha Signaling Pathway | |||||
B Cell Receptor Signaling Pathway | |||||
IL17 signaling pathway | |||||
TWEAK Signaling Pathway | |||||
Leptin signaling pathway | |||||
RANKL/RANK Signaling Pathway | |||||
Signalling by NGF | |||||
IL-1 signaling pathway | |||||
TCR signaling | |||||
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways | |||||
Interleukin-1 signaling | |||||
Apoptosis Modulation and Signaling | |||||
Type II diabetes mellitus | |||||
MicroRNAs in cardiomyocyte hypertrophy | |||||
Regulation of toll-like receptor signaling pathway | |||||
Osteopontin Signaling | |||||
NOD pathway | |||||
References | |||||
Ref 527173 | Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell Proliferation. J Pharmacol Exp Ther. 2005 Jan;312(1):373-81. Epub 2004 Aug 17. | ||||
Ref 528076 | A selective small molecule IkappaB Kinase beta inhibitor blocks nuclear factor kappaB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells. J Pharmacol Exp Ther. 2006 Jun;317(3):989-1001. Epub 2006 Mar 8. | ||||
Ref 531284 | Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. | ||||
Ref 532095 | Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73. | ||||
Ref 535043 | Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem. 2000 Nov 17;275(46):36062-6. | ||||
Ref 535178 | IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem. 2001 May 25;276(21):18223-8. Epub 2001 Mar 16. | ||||
Ref 535797 | A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum. 2003 Sep;48(9):2652-9. |
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