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KEGG   PATHWAY: hsa04064
Entry
hsa04064                    Pathway                                
Name
NF-kappa B signaling pathway - Homo sapiens (human)
Description
Nuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are several pathways leading to NF-kappa B-activation. The canonical pathway is induced by tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or byproducts of bacterial and viral infections. This pathway relies on IKK- mediated IkappaB-alpha phosphorylation on Ser32 and 36, leading to its degradation, which allows the p50/p65 NF-kappa B dimer to enter the nucleus and activate gene transcription. Atypical pathways are IKK-independent and rely on phosphorylation of IkappaB-alpha on Tyr42 or on Ser residues in IkappaB-alpha PEST domain. The non-canonical pathway is triggered by particular members of the TNFR superfamily, such as lymphotoxin-beta (LT-beta) or BAFF. It involves NIK and IKK-alpha-mediated p100 phosphorylation and processing to p52, resulting in nuclear translocation of p52/RelB heterodimers.
Class
Environmental Information Processing; Signal transduction
Pathway map
hsa04064  NF-kappa B signaling pathway
hsa04064

Network
  Element
N00151  TNF-NFKB signaling pathway
N00505  CD40-NFKB signaling pathway
N00559  LIGHT-HVEM-NFKB signaling pathway
N01797  EDA-EDAR signaling pathway
N01798  TNFSF11-TNFRSF11A signaling pathway
Drug
D00742  Etanercept (USAN/INN)
D00754  Thalidomide (JAN/USP/INN)
D01146  Iguratimod (JAN/INN)
D02979  Ardenermin (USAN)
D03068  Belimumab (USAN)
D04687  Lenalidomide (JAN/USAN/INN)
D04690  Lenercept (USAN/INN)
D05263  Onercept (USAN/INN)
D05393  Pegsunercept (USAN)
D06193  Toralizumab (USAN/INN)
D06619  Mifamurtide (USAN)
D06635  Rilonacept (USAN/INN)
D08562  Tasonermin (INN)
D08866  Baminercept (USAN/INN)
D08877  Briobacept (USAN)
D09347  Fostamatinib (USAN)
D09348  Fostamatinib disodium (USAN)
D09730  Olaparib (JAN/USAN/INN)
D09813  Lenalidomide hydrate (JAN)
D10733  Talazoparib tosylate (USAN)
D11122  Letolizumab (USAN/INN)
D11127  Tibulizumab (USAN/INN)
D11209  Entospletinib (USAN/INN)
D11457  Fenebrutinib (USAN/INN)
D11478  Branebrutinib (USAN)
D11703  Opinercept (INN)
D11789  Mivavotinib (USAN/INN)
D11790  Mivavotinib citrate (USAN)
D11873  Rilzabrutinib (JAN/USAN/INN)
D11907  Rozibafusp alfa (USAN/INN)
D12151  Ianalumab (USAN/INN)
D12158  Elsubrutinib (USAN/INN)
D12160  Orelabrutinib (USAN/INN)
D12167  Zimlovisertib (USAN)
D12181  Edasalonexent (USAN/INN)
D12213  Tolebrutinib (JAN/USAN/INN)
D12285  Remibrutinib (JAN/USAN/INN)
D12352  Eclitasertib (USAN/INN)
D12383  Edralbrutinib (USAN/INN)
D12411  Emavusertib (USAN/INN)
D12412  Emavusertib hydrochloride (USAN)
D12467  Evobrutinib (USAN/INN)
D12504  Nemtabrutinib (USAN/INN)
D12532  Emavusertib mesylate (USAN)
D12533  Emavusertib maleate (USAN)
D12538  Emavusertib phosphate (USAN)
D12539  emavusertib tosylate (USAN)
D12648  Quisovalimab (USAN/INN)
D12656  Adakitug (USAN)
D12821  Flizasertib (USAN/INN)
D12846  Ocadusertib (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3932  LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
7535  ZAP70; zeta chain of T cell receptor associated protein kinase 70 [KO:K07360] [EC:2.7.10.2]
27040  LAT; linker for activation of T cells [KO:K07362]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5588  PRKCQ; protein kinase C theta [KO:K18052] [EC:2.7.11.13]
102723407  IGH; immunoglobulin heavy variable 4-38-2-like [KO:K06856]
6850  SYK; spleen associated tyrosine kinase [KO:K05855] [EC:2.7.10.2]
4067  LYN; LYN proto-oncogene, Src family tyrosine kinase [KO:K05854] [EC:2.7.10.2]
29760  BLNK; B cell linker [KO:K07371]
695  BTK; Bruton tyrosine kinase [KO:K07370] [EC:2.7.10.2]
5336  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
29775  CARD10; caspase recruitment domain family member 10 [KO:K20912]
84433  CARD11; caspase recruitment domain family member 11 [KO:K07367]
79092  CARD14; caspase recruitment domain family member 14 [KO:K20913]
8915  BCL10; BCL10 immune signaling adaptor [KO:K07368]
10892  MALT1; MALT1 paracaspase [KO:K07369] [EC:3.4.22.-]
3553  IL1B; interleukin 1 beta [KO:K04519]
3554  IL1R1; interleukin 1 receptor type 1 [KO:K04386]
4615  MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729]
3654  IRAK1; interleukin 1 receptor associated kinase 1 [KO:K04730] [EC:2.7.11.1]
51135  IRAK4; interleukin 1 receptor associated kinase 4 [KO:K04733] [EC:2.7.11.1]
7189  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:2.3.2.27]
7124  TNF; tumor necrosis factor [KO:K03156]
7132  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
8737  RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]
8717  TRADD; TNFRSF1A associated via death domain [KO:K03171]
7186  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
7188  TRAF5; TNF receptor associated factor 5 [KO:K09849]
329  BIRC2; baculoviral IAP repeat containing 2 [KO:K16060]
330  BIRC3; baculoviral IAP repeat containing 3 [KO:K16060]
1896  EDA; ectodysplasin A [KO:K05480]
10913  EDAR; ectodysplasin A receptor [KO:K05162]
128178  EDARADD; EDAR associated via death domain [KO:K23324]
1540  CYLD; CYLD lysine 63 deubiquitinase [KO:K08601] [EC:3.4.19.12]
60401  EDA2R; ectodysplasin A2 receptor [KO:K05163]
23586  RIGI; RNA sensor RIG-I [KO:K12646] [EC:5.6.2.6]
7706  TRIM25; tripartite motif containing 25 [KO:K10652] [EC:2.3.2.27]
3929  LBP; lipopolysaccharide binding protein [KO:K05399]
929  CD14; CD14 molecule [KO:K04391]
7099  TLR4; toll like receptor 4 [KO:K10160]
23643  LY96; lymphocyte antigen 96 [KO:K05400]
114609  TIRAP; TIR domain containing adaptor protein [KO:K05403]
353376  TICAM2; TIR domain containing adaptor molecule 2 [KO:K05409]
148022  TICAM1; TIR domain containing adaptor molecule 1 [KO:K05842]
959  CD40LG; CD40 ligand [KO:K03161]
958  CD40; CD40 molecule [KO:K03160]
7187  TRAF3; TNF receptor associated factor 3 [KO:K03174]
8600  TNFSF11; TNF superfamily member 11 [KO:K05473]
8792  TNFRSF11A; TNF receptor superfamily member 11a [KO:K05147]
4049  LTA; lymphotoxin alpha [KO:K05468]
4050  LTB; lymphotoxin beta [KO:K03157]
8740  TNFSF14; TNF superfamily member 14 [KO:K05477]
4055  LTBR; lymphotoxin beta receptor [KO:K03159]
9020  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
10454  TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403]
23118  TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404]
257397  TAB3; TGF-beta activated kinase 1 (MAP3K7) binding protein 3 [KO:K12793]
10673  TNFSF13B; TNF superfamily member 13b [KO:K05476]
115650  TNFRSF13C; TNF receptor superfamily member 13C [KO:K05151]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
142  PARP1; poly(ADP-ribose) polymerase 1 [KO:K24070] [EC:2.4.2.30]
51588  PIAS4; protein inhibitor of activated STAT 4 [KO:K16065] [EC:2.3.2.27]
7329  UBE2I; ubiquitin conjugating enzyme E2 I [KO:K10577]
472  ATM; ATM serine/threonine kinase [KO:K04728] [EC:2.7.11.1]
55367  PIDD1; p53-induced death domain protein 1 [KO:K10130]
23085  ERC1; ELKS/RAB6-interacting/CAST family member 1 [KO:K16072]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
10848  PPP1R13L; protein phosphatase 1 regulatory subunit 13 like [KO:K27356]
8837  CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724]
331  XIAP; X-linked inhibitor of apoptosis [KO:K04725] [EC:2.3.2.27]
598  BCL2L1; BCL2 like 1 [KO:K04570]
596  BCL2; BCL2 apoptosis regulator [KO:K02161]
1647  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
4616  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
10912  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
7185  TRAF1; TNF receptor associated factor 1 [KO:K03172]
597  BCL2A1; BCL2 related protein A1 [KO:K02162]
4791  NFKB2; nuclear factor kappa B subunit 2 [KO:K04469]
3576  CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030]
7128  TNFAIP3; TNF alpha induced protein 3 [KO:K11859] [EC:3.4.19.12]
5743  PTGS2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:1.14.99.1]
6351  CCL4; C-C motif chemokine ligand 4 [KO:K12964]
9560  CCL4L2; C-C motif chemokine ligand 4 like 2 [KO:K12964]
388372  CCL4L1; C-C motif chemokine ligand 4 like 1 [KO:K12964]
2919  CXCL1; C-X-C motif chemokine ligand 1 [KO:K05505]
2920  CXCL2; C-X-C motif chemokine ligand 2 [KO:K05505]
2921  CXCL3; C-X-C motif chemokine ligand 3 [KO:K05505]
7412  VCAM1; vascular cell adhesion molecule 1 [KO:K06527]
5328  PLAU; plasminogen activator, urokinase [KO:K01348] [EC:3.4.21.73]
1457  CSNK2A1; casein kinase 2 alpha 1 [KO:K03097] [EC:2.7.11.1]
1459  CSNK2A2; casein kinase 2 alpha 2 [KO:K03097] [EC:2.7.11.1]
283106  CSNK2A3; casein kinase 2 alpha 3 [KO:K03097] [EC:2.7.11.1]
1460  CSNK2B; casein kinase 2 beta [KO:K03115]
5971  RELB; RELB proto-oncogene, NF-kB subunit [KO:K09253]
6357  CCL13; C-C motif chemokine ligand 13 [KO:K16595]
6363  CCL19; C-C motif chemokine ligand 19 [KO:K05512]
6366  CCL21; C-C motif chemokine ligand 21 [KO:K16062]
6387  CXCL12; C-X-C motif chemokine ligand 12 [KO:K10031]
3383  ICAM1; intercellular adhesion molecule 1 [KO:K06490]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:21772278
  Authors
Oeckinghaus A, Hayden MS, Ghosh S
  Title
Crosstalk in NF-kappaB signaling pathways.
  Journal
Nat Immunol 12:695-708 (2011)
DOI:10.1038/ni.2065
Reference
PMID:19203223
  Authors
Gloire G, Piette J
  Title
Redox regulation of nuclear post-translational modifications during NF-kappaB activation.
  Journal
Antioxid Redox Signal 11:2209-22 (2009)
DOI:10.1089/ARS.2009.2463
Reference
PMID:17183360
  Authors
Perkins ND
  Title
Integrating cell-signalling pathways with NF-kappaB and IKK function.
  Journal
Nat Rev Mol Cell Biol 8:49-62 (2007)
DOI:10.1038/nrm2083
Reference
PMID:16264088
  Authors
Lindstrom TM, Bennett PR
  Title
The role of nuclear factor kappa B in human labour.
  Journal
Reproduction 130:569-81 (2005)
DOI:10.1530/rep.1.00197
Reference
PMID:22017430
  Authors
Razani B, Reichardt AD, Cheng G
  Title
Non-canonical NF-kappaB signaling activation and regulation: principles and perspectives.
  Journal
Immunol Rev 244:44-54 (2011)
DOI:10.1111/j.1600-065X.2011.01059.x
Reference
PMID:21173796
  Authors
Sun SC
  Title
Non-canonical NF-kappaB signaling pathway.
  Journal
Cell Res 21:71-85 (2011)
DOI:10.1038/cr.2010.177
Reference
PMID:17431096
  Authors
Neumann M, Naumann M
  Title
Beyond IkappaBs: alternative regulation of NF-kappaB activity.
  Journal
FASEB J 21:2642-54 (2007)
DOI:10.1096/fj.06-7615rev
Reference
PMID:22119011
  Authors
Verhelst K, Carpentier I, Beyaert R
  Title
Regulation of TNF-induced NF-kappaB activation by different cytoplasmic ubiquitination events.
  Journal
Cytokine Growth Factor Rev 22:277-86 (2011)
DOI:10.1016/j.cytogfr.2011.11.002
Reference
PMID:22017435
  Authors
Rickert RC, Jellusova J, Miletic AV
  Title
Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease.
  Journal
Immunol Rev 244:115-33 (2011)
DOI:10.1111/j.1600-065X.2011.01067.x
Reference
PMID:21232019
  Authors
Naude PJ, den Boer JA, Luiten PG, Eisel UL
  Title
Tumor necrosis factor receptor cross-talk.
  Journal
FEBS J 278:888-98 (2011)
DOI:10.1111/j.1742-4658.2011.08017.x
Reference
PMID:16984817
  Authors
Grivennikov SI, Kuprash DV, Liu ZG, Nedospasov SA
  Title
Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms.
  Journal
Int Rev Cytol 252:129-61 (2006)
DOI:10.1016/S0074-7696(06)52002-9
Reference
PMID:16356770
  Authors
Wada T, Nakashima T, Hiroshi N, Penninger JM
  Title
RANKL-RANK signaling in osteoclastogenesis and bone disease.
  Journal
Trends Mol Med 12:17-25 (2006)
DOI:10.1016/j.molmed.2005.11.007
Reference
PMID:17098202
  Authors
Schulze-Luehrmann J, Ghosh S
  Title
Antigen-receptor signaling to nuclear factor kappa B.
  Journal
Immunity 25:701-15 (2006)
DOI:10.1016/j.immuni.2006.10.010
Reference
PMID:15134788
  Authors
Weil R, Israel A
  Title
T-cell-receptor- and B-cell-receptor-mediated activation of NF-kappaB in lymphocytes.
  Journal
Curr Opin Immunol 16:374-81 (2004)
DOI:10.1016/j.coi.2004.03.003
Reference
PMID:15905862
  Authors
Siebenlist U, Brown K, Claudio E
  Title
Control of lymphocyte development by nuclear factor-kappaB.
  Journal
Nat Rev Immunol 5:435-45 (2005)
DOI:10.1038/nri1629
Reference
PMID:14657271
  Authors
Lucas PC, McAllister-Lucas LM, Nunez G
  Title
NF-kappaB signaling in lymphocytes: a new cast of characters.
  Journal
J Cell Sci 117:31-9 (2004)
DOI:10.1242/jcs.00904
Reference
PMID:19726767
  Authors
Khan WN
  Title
B cell receptor and BAFF receptor signaling regulation of B cell homeostasis.
  Journal
J Immunol 183:3561-7 (2009)
DOI:10.4049/jimmunol.0800933
Reference
PMID:19302050
  Authors
Vallabhapurapu S, Karin M
  Title
Regulation and function of NF-kappaB transcription factors in the immune system.
  Journal
Annu Rev Immunol 27:693-733 (2009)
DOI:10.1146/annurev.immunol.021908.132641
Reference
PMID:17047224
  Authors
Hacker H, Karin M
  Title
Regulation and function of IKK and IKK-related kinases.
  Journal
Sci STKE 2006:re13 (2006)
DOI:10.1126/stke.3572006re13
Reference
PMID:21872579
  Authors
Sabatel H, Pirlot C, Piette J, Habraken Y
  Title
Importance of PIKKs in NF-kappaB activation by genotoxic stress.
  Journal
Biochem Pharmacol 82:1371-83 (2011)
DOI:10.1016/j.bcp.2011.07.105
Reference
PMID:21187855
  Authors
Miyamoto S
  Title
Nuclear initiated NF-kappaB signaling: NEMO and ATM take center stage.
  Journal
Cell Res 21:116-30 (2011)
DOI:10.1038/cr.2010.179
Reference
PMID:18832076
  Authors
Brzoska K, Szumiel I
  Title
Signalling loops and linear pathways: NF-kappaB activation in response to genotoxic stress.
  Journal
Mutagenesis 24:1-8 (2009)
DOI:10.1093/mutage/gen056
Reference
PMID:17607554
  Authors
Wu ZH, Miyamoto S
  Title
Many faces of NF-kappaB signaling induced by genotoxic stress.
  Journal
J Mol Med (Berl) 85:1187-202 (2007)
DOI:10.1007/s00109-007-0227-9
Reference
PMID:22390971
  Authors
Maelfait J, Beyaert R
  Title
Emerging role of ubiquitination in antiviral RIG-I signaling.
  Journal
Microbiol Mol Biol Rev 76:33-45 (2012)
DOI:10.1128/MMBR.05012-11
Reference
PMID:18613837
  Authors
Ware CF
  Title
Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways.
  Journal
Immunol Rev 223:186-201 (2008)
DOI:10.1111/j.1600-065X.2008.00629.x
Reference
PMID:15546385
  Authors
Schneider K, Potter KG, Ware CF
  Title
Lymphotoxin and LIGHT signaling pathways and target genes.
  Journal
Immunol Rev 202:49-66 (2004)
DOI:10.1111/j.0105-2896.2004.00206.x
Reference
PMID:22152226
  Authors
Remouchamps C, Boutaffala L, Ganeff C, Dejardin E
  Title
Biology and signal transduction pathways of the Lymphotoxin-alphabeta/LTbetaR system.
  Journal
Cytokine Growth Factor Rev 22:301-10 (2011)
DOI:10.1016/j.cytogfr.2011.11.007
Reference
PMID:21135871
  Authors
Liu S, Chen ZJ
  Title
Expanding role of ubiquitination in NF-kappaB signaling.
  Journal
Cell Res 21:6-21 (2011)
DOI:10.1038/cr.2010.170
Reference
PMID:19489733
  Authors
Skaug B, Jiang X, Chen ZJ
  Title
The role of ubiquitin in NF-kappaB regulatory pathways.
  Journal
Annu Rev Biochem 78:769-96 (2009)
DOI:10.1146/annurev.biochem.78.070907.102750
Reference
PMID:20300215
  Authors
Wertz IE, Dixit VM
  Title
Signaling to NF-kappaB: regulation by ubiquitination.
  Journal
Cold Spring Harb Perspect Biol 2:a003350 (2010)
DOI:10.1101/cshperspect.a003350
Reference
PMID:11875461
  Authors
Karin M, Lin A
  Title
NF-kappaB at the crossroads of life and death.
  Journal
Nat Immunol 3:221-7 (2002)
DOI:10.1038/ni0302-221
Reference
PMID:12654254
  Authors
Lin A, Karin M
  Title
NF-kappaB in cancer: a marked target.
  Journal
Semin Cancer Biol 13:107-14 (2003)
DOI:10.1016/S1044-579X(02)00128-1
Reference
PMID:16251197
  Authors
Morlon A, Munnich A, Smahi A
  Title
TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.
  Journal
Hum Mol Genet 14:3751-7 (2005)
DOI:10.1093/hmg/ddi405
Reference
PMID:24070496
  Authors
Sadier A, Viriot L, Pantalacci S, Laudet V
  Title
The ectodysplasin pathway: from diseases to adaptations.
  Journal
Trends Genet 30:24-31 (2014)
DOI:10.1016/j.tig.2013.08.006
Reference
PMID:26260321
  Authors
Verhelst K, Gardam S, Borghi A, Kreike M, Carpentier I, Beyaert R
  Title
XEDAR activates the non-canonical NF-kappaB pathway.
  Journal
Biochem Biophys Res Commun 465:275-80 (2015)
DOI:10.1016/j.bbrc.2015.08.019
Reference
PMID:27508514
  Authors
McDaniel DK, Eden K, Ringel VM, Allen IC
  Title
Emerging Roles for Noncanonical NF-kappaB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology.
  Journal
Inflamm Bowel Dis 22:2265-79 (2016)
DOI:10.1097/MIB.0000000000000858
Reference
PMID:12787560
  Authors
Mikkola ML, Thesleff I
  Title
Ectodysplasin signaling in development.
  Journal
Cytokine Growth Factor Rev 14:211-24 (2003)
DOI:10.1016/S1359-6101(03)00020-0
Reference
PMID:26646590
  Authors
Hu Y, Ge W, Wang X, Sutendra G, Zhao K, Dedeic Z, Slee EA, Baer C, Lu X
  Title
Caspase cleavage of iASPP potentiates its ability to inhibit p53 and NF-kappaB.
  Journal
Oncotarget 6:42478-90 (2015)
DOI:10.18632/oncotarget.6478
Related
pathway
hsa03050  Proteasome
hsa04020  Calcium signaling pathway
hsa04060  Cytokine-cytokine receptor interaction
hsa04120  Ubiquitin mediated proteolysis
hsa04210  Apoptosis
hsa04380  Osteoclast differentiation
hsa04620  Toll-like receptor signaling pathway
hsa04622  RIG-I-like receptor signaling pathway
hsa04660  T cell receptor signaling pathway
hsa04662  B cell receptor signaling pathway
KO pathway
ko04064   

  All links  
Network (5)   
   KEGG NETWORK (5)   
Genome (1)   
   KEGG GENOME (1)   
Gene (105)   
   KEGG GENES (105)   
All databases (111)   

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