Pathway maps

Transcription_NF-kB signaling pathway
Transcription_NF-kB signaling pathway

Object List (links open in MetaCore):

TNF-R1, IL1RAP, IRAKM, TRAF2, SITPEC (ECSIT), Ubiquitin, IL-1RI, IKK-beta, I-kB, LTBR(TNFRSF3), SUMO-1, IRAK1/2, CD28, NF-kB p52/RelB, TNF-alpha, TNF-beta, NF-kB2 (p100), LBP, MD-2, CD14, IL-1 alpha, TLR4, MyD88, TCR alpha/beta, TOLLIP, RIPK2, TRADD, AKT(PKB), TRAF6, IKK (cat), IKAP, PKC-theta, IKK-alpha, LPS, NIK(MAP3K14), NF-kB, MEKK1(MAP3K1), IKK-gamma

Description

NF-kB signaling pathway

The Nuclear factor kappa B ( NF-kB ) plays a crucial role in immune and inflammatory responses through the regulation of genes encoding pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and inducible enzymes. Transcription factors of the NF-kB family are activated in response to signals that lead to cell growth, differentiation, apoptosis and other events. NF-kB is activated by signals that activate Nuclear factor NF-kappa-B inhibitor kinase ( IKK ) resulting in the phosphorylation of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB ), this targets I-kB for degradation in the proteasome and frees the NF-kB dimer, which then translocates to the nucleus and activates target genes [1].

Tumor necrosis factor ( TNF-alpha ) activates NF-kB via canonical phosphorylation of IKK mediated by TNFRSF1A-associated via death domain ( TRADD )/ TNF receptor-associated factor 2 ( TRAF2 )/ Mitogen-activated protein kinase kinase kinase 14 ( NIK(MAP3K14) ) [2]. The non-canonical pathway of NF-kB activation is utilized in response to the ligation of only certain TNF receptor superfamily members, for example Lymphotoxin beta receptor ( LTBR(TNFRSF3) ). In the non-canonical pathway, TRAF stimulates NIK, which subsequently activates IKK-alpha by phosphorylation. IKK-alpha promotes the processing of nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 ( NF-kB2 (p100) ) from p100 to p52 form. Further processed NF-kB2 is bound to V-rel reticuloendotheliosis viral oncogene homolog B ( RelB ). NF-kB p52/RelB dimer is translocated into the nucleus to affect gene transcription. The non-canonical pathway is independent on IKK-beta and IKK-gamma [3], [1].

T cell receptor ( TCR ) and CD28 molecule ( CD28 ) can stimulate NF-KB via Protein kinase C theta ( PKC-theta )-dependent pathway [4], [5], [6]. Also CD28 triggers V-akt murine thymoma viral oncogene homolog 1 ( AKT )-mediated pathway [5].

Upon binding of Interleukin 1 ( IL-1 ), the Interleukin 1 receptor type I ( IL-1RI ) associates with Interleukin 1 receptor accessory protein ( IL1RAP ), forming a functional signaling receptor complex that recruits myeloid differentiation primary response gene 88 ( MyD88 ). This leads to the translocation into this complex of Interleukin-1 receptor-associated kinase ( IRAK1/2 ) together with Toll interacting protein ( TOLLIP ). IRAK1 binds TNF receptor-associated factor 6 ( TRAF6 ). After dissociation from the receptor complex, IRAK1/ TRAF6 induces NIK or Mitogen-activated protein kinase kinase kinase 1 ( MEKK1(MAP3K1) )-dependent phosphorylation of IKK [7].

Lipopolysacccharide ( LPS ) in complex with Lipopolysaccharide binding protein ( LBP ) binds CD14 molecule ( CD14 ) on the cell membrane. It transfers LPS to lymphocyte antigen 96 ( MD- 2 ) and Toll-like receptor 4 ( TLR4 ). TLR4 via binding MyD88 [7] and/or possibly Receptor-interacting serine-threonine kinase 2 ( RIPK2 ) induces NF-kB -activating cascade [8].

References:

  1. Liang Y, Zhou Y, Shen P
    NF-kappaB and its regulation on the immune system. Cellular & molecular immunology 2004 Oct;1(5):343-50
  2. Ding WX, Yin XM
    Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. Journal of cellular and molecular medicine 2004 Oct-Dec;8(4):445-54
  3. Orange JS, Levy O, Geha RS
    Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunological reviews 2005 Feb;203:21-37
  4. Coudronniere N, Villalba M, Englund N, Altman A
    NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta. Proceedings of the National Academy of Sciences of the United States of America 2000 Mar 28;97(7):3394-9
  5. Schmitz ML, Bacher S, Dienz O
    NF-kappaB activation pathways induced by T cell costimulation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Dec;17(15):2187-93
  6. Li Y, Sedwick CE, Hu J, Altman A
    Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation. The Journal of biological chemistry 2005 Jan 14;280(2):1217-23
  7. Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R
    TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cellular and molecular life sciences : CMLS 2008 Oct;65(19):2964-78
  8. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, Medzhitov R, Flavell RA
    RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 2002 Mar 14;416(6877):194-9