KEGG   PATHWAY: ko04064
Entry
ko04064                     Pathway                                
Name
NF-kappa B signaling pathway
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
ko04064  NF-kappa B signaling pathway
ko04064

Orthology
K10784  T cell receptor alpha chain V region
K10785  T-cell receptor beta chain V region
K05856  lymphocyte cell-specific protein tyrosine kinase [EC:2.7.10.2]
K07360  tyrosine-protein kinase ZAP-70 [EC:2.7.10.2]
K07362  linker for activation of T cells family member 1
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K18052  novel protein kinase C theta type [EC:2.7.11.13]
K06856  immunoglobulin heavy chain
K05855  spleen tyrosine kinase [EC:2.7.10.2]
K05854  tyrosine-protein kinase Lyn [EC:2.7.10.2]
K07371  B-cell linker protein
K07370  Bruton agammaglobulinemia tyrosine kinase [EC:2.7.10.2]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K20912  caspase recruitment domain-containing protein 10
K07367  caspase recruitment domain-containing protein 11
K20913  caspase recruitment domain-containing protein 14
K07368  B-cell CLL/lymphoma 10
K07369  mucosa-associated lymphoid tissue lymphoma translocation protein 1 [EC:3.4.22.-]
K04519  interleukin 1 beta
K04386  interleukin 1 receptor type I
K04729  myeloid differentiation primary response protein MyD88
K04730  interleukin-1 receptor-associated kinase 1 [EC:2.7.11.1]
K04733  interleukin-1 receptor-associated kinase 4 [EC:2.7.11.1]
K03175  TNF receptor-associated factor 6 [EC:2.3.2.27]
K03156  tumor necrosis factor superfamily, member 2
K03158  tumor necrosis factor receptor superfamily member 1A
K02861  receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1]
K03171  tumor necrosis factor receptor type 1-associated DEATH domain protein
K03173  TNF receptor-associated factor 2 [EC:2.3.2.27]
K09849  TNF receptor-associated factor 5
K16060  baculoviral IAP repeat-containing protein 2/3
K05480  ectodysplasin-A
K05162  tumor necrosis factor receptor superfamily member EDAR
K23324  ectodysplasin-A receptor-associated adapter protein
K08601  ubiquitin carboxyl-terminal hydrolase CYLD [EC:3.4.19.12]
K05163  tumor necrosis factor receptor superfamily member 27
K12646  ATP-dependent RNA helicase DDX58 [EC:3.6.4.13]
K10652  tripartite motif-containing protein 25 [EC:2.3.2.27]
K05399  lipopolysaccharide-binding protein
K04391  monocyte differentiation antigen CD14
K10160  toll-like receptor 4
K05400  lymphocyte antigen 96
K05403  toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
K05409  TRIF-related adaptor molecule
K05842  toll-like receptor adapter molecule 1
K03161  tumor necrosis factor ligand superfamily member 5
K03160  tumor necrosis factor receptor superfamily member 5
K03174  TNF receptor-associated factor 3
K05473  tumor necrosis factor ligand superfamily member 11
K05147  tumor necrosis factor receptor superfamily member 11A
K05468  lymphotoxin alpha (TNF superfamily, member 1)
K03157  lymphotoxin beta (TNF superfamily, member 3)
K05477  tumor necrosis factor ligand superfamily member 14
K03159  lymphotoxin beta receptor TNFR superfamily member 3
K04466  mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25]
K04427  mitogen-activated protein kinase kinase kinase 7 [EC:2.7.11.25]
K04403  TAK1-binding protein 1
K04404  TAK1-binding protein 2
K12793  TAK1-binding protein 3
K05476  tumor necrosis factor ligand superfamily member 13B
K05151  tumor necrosis factor receptor superfamily member 13C
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K24070  poly [ADP-ribose] polymerase 1 [EC:2.4.2.30]
K16065  E3 SUMO-protein ligase PIAS4 [EC:2.3.2.27]
K10577  ubiquitin-conjugating enzyme E2 I
K04728  serine-protein kinase ATM [EC:2.7.11.1]
K10130  leucine-rich repeats and death domain-containing protein
K16072  ELKS/RAB6-interacting/CAST family member 1
K04734  NF-kappa-B inhibitor alpha
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K27356  RelA-associated inhibitor
K04724  CASP8 and FADD-like apoptosis regulator
K04725  E3 ubiquitin-protein ligase XIAP [EC:2.3.2.27]
K04570  Bcl-2-like 1 (apoptosis regulator Bcl-X)
K02161  apoptosis regulator Bcl-2
K04402  growth arrest and DNA-damage-inducible protein
K03172  TNF receptor-associated factor 1
K02162  hematopoietic Bcl-2-related protein A1
K04469  nuclear factor of kappa light polypeptide gene enhancer in B-cells 2
K10030  interleukin 8
K11859  tumor necrosis factor, alpha-induced protein 3 [EC:3.4.19.12]
K11987  prostaglandin-endoperoxide synthase 2 [EC:1.14.99.1]
K12964  C-C motif chemokine 4
K05505  C-X-C motif chemokine 1/2/3
K06527  vascular cell adhesion molecule 1
K01348  urokinase plasminogen activator [EC:3.4.21.73]
K03097  casein kinase II subunit alpha [EC:2.7.11.1]
K03115  casein kinase II subunit beta
K09253  transcription factor RelB
K16595  C-C motif chemokine 13
K05512  C-C motif chemokine 19
K16062  C-C motif chemokine 21
K10031  C-X-C motif chemokine 12
K06490  intercellular adhesion molecule 1
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
  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
  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
  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
  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
  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
  Authors
Sun SC
  Title
Non-canonical NF-kappaB signaling pathway.
  Journal
Cell Res 21:71-85 (2011)
DOI:10.1038/cr.2010.177
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
ko03050  Proteasome
ko04020  Calcium signaling pathway
ko04060  Cytokine-cytokine receptor interaction
ko04120  Ubiquitin mediated proteolysis
ko04210  Apoptosis
ko04380  Osteoclast differentiation
ko04620  Toll-like receptor signaling pathway
ko04622  RIG-I-like receptor signaling pathway
ko04660  T cell receptor signaling pathway
ko04662  B cell receptor signaling pathway
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