Pathway maps

Apoptosis and survival_TNFR1 signaling pathway
Apoptosis and survival_TNFR1 signaling pathway

Object List (links open in MetaCore):

ARTS-1, HtrA2, BRE, tBid, FLASH, c-Jun, TNF-R1, Caspase-9, Caspase-2, c-IAP1, c-IAP2, FADD, jBid, Apaf-1, JNK (MAPK8-10), XIAP, Caspase-3, c-FLIP (S), IKK-gamma, Bid, RIPK1, Smac/Diablo, Caspase-6, Bid = jBid, NF-kB, MEK4 (MAP2K4), MEKK1 (MAP3K1), Caspase-8, Cytochrome c, IKK (cat), Caspase-7, I-kB, TRADD, MKK7 (MAP2K7), Bid = tBid, RAIDD, TNF-alpha, Bax, SODD, Bcl-2, TRAF2, GCK (MAP4K2), Caspase-10


Role TNF-alpha in apoptosis

The tumor necrosis factor ( TNF-alpha ) is a potent cytokine produced by many cell types, including macrophages, monocytes, lymphocytes, keratinocytes and fibroblasts, in response to inflammation, infection, injury and other environmental challenges. TNF-alpha elicits a particularly broad spectrum of organismal and cellular responses of cell proliferation, differentiation and apoptosis [1].

TNF-alpha exerts its effects through two distinct receptors, TNFR1 and TNFR2 . Binding of the inherently trimeric TNF-alpha to TNFR1 induces receptor trimerization and recruitment of TNFR1-associated death domain protein ( TRADD), which serves as a platform to recruit at least three additional mediators: receptor-interacting protein 1 ( RIP1 ), Fas-associated death domain protein ( FADD ), TNF-receptor-associated factor 2 ( TRAF2 ). The adaptor protein transmits an activating signal from the activated receptor TNFR1 to some signaling cascades - caspase cascade with subsequent apoptosis, NF-kB activating cascade and JNK cascade [1].

Recruiting of FADD and RIPK by TRADD results in activation of the caspase cascade followed by apoptosis. Adaptor proteins FADD and RAIDD participate in activation of initiator caspases caspase-2, -8, and -10 by the activated receptor TNFR1. Initiator caspases cleave and activate effector caspases caspases-3, -6 and -7. Effector caspases are responsible for the proteolytic cleavage of a broad spectrum of cellular targets, which ultimately leads to cell death [1], [2].

Recruiting of TRAF2 and RIPK by TRADD lead to an activation of survival transcription factor NF-kB. RIPK and TRAF2 recruit IKK-gamma and IKK alpha/beta subunits of IKK (inhibitor of nuclear factor kappa B kinase ) complex respectively [3], [4]. It was shown that RIPK1 and TRAF2 both are necessary for IKK activation [5].

The NF-kB pathway might intersect with the apoptotic pathway via induction of antiapoptotic protein BCL-2 and cellular inhibitors of apoptosis ( c-IAP1, c-IAP1, XIAP ), which function as specific caspase inhibitors [6], [7]. Moreover, c-IAP1 and TRAF2 form a complex which direct inhibites of caspase-8 cleavage and activation under TNF-alpha signaling [8].

TNF-alpha also activates the JNK signaling cascade and results in an activation of the transcription factor AP-1 and subsequent increase proliferation. TRAF2 interact with and activate MEKK1 activating JNK cascade [9].

Involvement of the JNK cascade in TNF-alpha -mediated apoptosis is controversial.

It was shown that TNF-alpha -induced activation of JNK results in the cleavage of apoptotic protein Bid at the 25 position amino acid. A specific Bid cleavage product ( jBid ) approximately 21 kDa in size subsequently translocates in the mitochondria and is capable to release Smac/DIABLO (mitochondrial Smac protein) from mitochondria without affecting the cytochrome c localisation [10]. In the cytoplasm, Smac/DIABLO binds XIAP, c-IAP1, c-IAP2, and abolishes the inhibitory action on caspases [6]. Additionally, Smac/DIABLO acts on and disrupts the TRAF2 - c-IAP1 complex and abolish its inhibition on caspase-8 [10].

Some regulators of TNF-alpha -signaling were detected. Silencer of death domain ( SODD ) binds TNFR1 and prevents self-aggregation and spontaneous downstream signaling at ligand absent.

SODD dissociates from TNFR1 upon receptor ligation [11].

BRE (brain and reproductive organ-expressed protein) inhibits both TNF-alpha- induced activation of NF-kB and apoptotic pathways [12].

ARTS-1 (aminopeptidase regulator of TNFR1 shedding) increases TNFR1 shedding and decreases membrane-associated TNFR1, thereby decreases the TNF-alpha signal [13].


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    Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology 2001 Sep;11(9):372-7
  2. Shearwin-Whyatt LM, Harvey NL, Kumar S
    Subcellular localization and CARD-dependent oligomerization of the death adaptor RAIDD. Cell death and differentiation 2000 Feb;7(2):155-65
  3. Zhang SQ, Kovalenko A, Cantarella G, Wallach D
    Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity 2000 Mar;12(3):301-11
  4. Devin A, Lin Y, Yamaoka S, Li Z, Karin M, Liu Zg
    The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Molecular and cellular biology 2001 Jun;21(12):3986-94
  5. Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu Z
    The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 2000 Apr;12(4):419-29
  6. Salvesen GS, Duckett CS
    IAP proteins: blocking the road to death's door. Nature reviews. Molecular cell biology. 2002 Jun;3(6):401-10
  7. Catz SD, Johnson JL
    Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 2001 Nov 1;20(50):7342-51
  8. Park YC, Ye H, Hsia C, Segal D, Rich RL, Liou HC, Myszka DG, Wu H
    A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell 2000 Jun 23;101(7):777-87
  9. Chadee DN, Yuasa T, Kyriakis JM
    Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Molecular and cellular biology 2002 Feb;22(3):737-49
  10. Deng Y, Ren X, Yang L, Lin Y, Wu X
    A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell 2003 Oct 3;115(1):61-70
  11. Miki K, Eddy EM
    Tumor necrosis factor receptor 1 is an ATPase regulated by silencer of death domain. Molecular and cellular biology 2002 Apr;22(8):2536-43
  12. Li Q, Ching AK, Chan BC, Chow SK, Lim PL, Ho TC, Ip WK, Wong CK, Lam CW, Lee KK, Chan JY, Chui YL
    A death receptor-associated anti-apoptotic protein, BRE, inhibits mitochondrial apoptotic pathway. The Journal of biological chemistry 2004 Dec 10;279(50):52106-16
  13. Cui X, Hawari F, Alsaaty S, Lawrence M, Combs CA, Geng W, Rouhani FN, Miskinis D, Levine SJ
    Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. The Journal of clinical investigation 2002 Aug;110(4):515-26