Pathway maps

Apoptosis and survival_Apoptotic TNF-family pathways
Apoptosis and survival_Apoptotic TNF-family pathways

Object List (links open in MetaCore):

NGFR (TNFRSF16), TRADD, TWEAK(TNFSF12), Bid = tBid, GITR (TNFRSF18), CD70(TNFSF7), Caspase-7, Caspase-9, RAIDD, Bcl-XL, DR4 (TNFRSF10A), TNF-alpha, LIGHT(TNFSF14), FADD, FasR (CD95), TRAF2, Caspase-10, FasL(TNFSF6), BAX, Bcl-2, RIPK1, tBid, TRAF3, NADE (NGFRAP1), DR6 (TNFRSF21), LTBR (TNFRSF3), XIAP, CD27BP, Caspase-8, Apo-2L(TNFSF10), Caspase-3, TNFSF18, TNF-R1, DR5 (TNFRSF10B), Smac/Diablo, NGF, CD27 (TNFRSF7), TNF-R2, Bid, DR3 (TNFRSF12), Caspase-2, c-IAP1


Apoptotic TNF-family pathways

Members of the tumour necrosis factor ligand family (TNFs) induce both apoptotic and anti-apoptotic pathways. TNFs transduce cellular responses through activation of different TNF-receptors (TNFRs) [1], [2], [3].

Different TNF/TNFRs may activate some pro-apoptotic proteins (e.g. members of the cysteine-aspartic acid protease (caspase) family) or inhibit some anti-apoptotic proteins (e.g. members of the Bcl-2 family). Thus, TNF/TNFRs exert influence on apoptosis via caspase cascade and via mitochondrial proteins [3].

Apoptotic signals from TNFR superfamily, member 1A ( TNF-R1 ) [4], TNFR superfamily, member 12 ( DR3 ) [5], TNFR superfamily, member 10a ( DR4 ) [6], TNFR superfamily, member 10b ( DR5 ) [7] and, possibly, TNFR superfamily, member 21 ( DR6 ) [7] are mediated by TNFRSF1A-associated via death domain ( TRADD ) and/or Fas (TNFRSF6)-associated via death domain ( FADD ). Receptor TNFR-interacting serine-threonine kinase 1 ( RIPK1 ) may participate in this signal transduction as well [8].

TNF-alpha/ TNFR superfamily, member 1B ( TNF-R2 ) signal transduction is mediated by a complex of intracellular signaling molecules including TNF receptor-associated factor 2 ( TRAF2 ) and RIPK1 [9], [10].

Adaptor proteins, such as FADD, TRADD and RIPK1 domain containing adaptor with death domain ( RAIDD ) transmit an activation signal to effectors caspases Caspase-2, -8, and -10 [11].

In other pathways, TNF/TNFRs' signal transduction is influenced via inhibition of anti-apoptotic protein members of the Bcl-2 and IAP families; e.g. B-cell CLL/lymphoma 2 ( Bcl-2 ) and BCL2-like 1 ( Bcl-XL ) baculoviral IAP repeat-containing 2 ( c-IAP1 ), baculoviral IAP repeat-containing 4 ( XIAP ).

For example, TNF superfamily, member 6 ( LIGHT )/ TNFR superfamily, member 3 ( LTBR ) signal transduction are mediated by a complex of intracellular signaling molecules including TRAF2, TNF receptor-associated factor 2 ( TRAF3 ), c-IAP1 and diablo homolog ( Smac/Diablo ) [12]. Smac/Diablo inhibits activity of anti-apoptotic proteins c-IAP1 and XIAP [13].

Nerve growth factor, beta polypeptide ( NGF )/ TNFR superfamily, member 16 ( NGFR ) apoptotic signal may be mediated via different mechanisms. One such mechanism is an activation of nerve growth factor receptor associated protein 1 ( NADE ) [14].

TNF superfamily, member 7 ( CD70 )/ TNFR superfamily, member 7 ( CD27 ) and TNF superfamily, member 18 ( TNFSF18 )/ TNFR superfamily, member 18 ( GITR ) signal transductions are mediated by a CD27-binding (Siva) protein ( CD27BP ) [15], [16]. CD27BP induces apoptosis via inhibition of anti-apoptotic proteins Bcl-2 and Bcl-XL [17], [18].


  1. Darnay BG, Aggarwal BB
    Signal transduction by tumour necrosis factor and tumour necrosis factor related ligands and their receptors. Annals of the rheumatic diseases 1999 Nov;58 Suppl 1:I2-I13
  2. Beletsky IP, Moshnikova AB, Proussakova OV
    Cytotoxic signal transduction pathways via TNF family receptors. Biochemistry. Biokhimii inverted question marka inverted question mark. 2002 Mar;67(3):312-28
  3. Lavrik I, Golks A, Krammer PH
    Death receptor signaling. Journal of cell science 2005 Jan 15;118(Pt 2):265-7
  4. Baud V, Karin M
    Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology 2001 Sep;11(9):372-7
  5. Chinnaiyan AM, O'Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, Xing L, Gentz R, Ni J, Dixit VM
    Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 1996 Nov 8;274(5289):990-2
  6. Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L
    Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 1997 Dec;7(6):821-30
  7. Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A
    Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000 Jun;12(6):611-20
  8. Meylan E, Tschopp J
    The RIP kinases: crucial integrators of cellular stress. Trends in biochemical sciences 2005 Mar;30(3):151-9
  9. Pimentel-Muinos FX, Seed B
    Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity 1999 Dec;11(6):783-93
  10. MacEwan DJ
    TNF ligands and receptors--a matter of life and death. British journal of pharmacology 2002 Feb;135(4):855-75
  11. Riedl SJ, Shi Y
    Molecular mechanisms of caspase regulation during apoptosis. Nature reviews. Molecular cell biology. 2004 Nov;5(11):897-907
  12. Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin LL
    Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. The Journal of biological chemistry 2003 Apr 18;278(16):14363-9
  13. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL
    Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000 Jul 7;102(1):43-53
  14. Mukai J, Hachiya T, Shoji-Hoshino S, Kimura MT, Nadano D, Suvanto P, Hanaoka T, Li Y, Irie S, Greene LA, Sato TA
    NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. The Journal of biological chemistry 2000 Jun 9;275(23):17566-70
  15. Spinicelli S, Nocentini G, Ronchetti S, Krausz LT, Bianchini R, Riccardi C
    GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. Cell death and differentiation 2002 Dec;9(12):1382-4
  16. Py B, Slomianny C, Auberger P, Petit PX, Benichou S
    Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway. Journal of immunology (Baltimore, Md. : 1950) 2004 Apr 1;172(7):4008-17
  17. Xue L, Chu F, Cheng Y, Sun X, Borthakur A, Ramarao M, Pandey P, Wu M, Schlossman SF, Prasad KV
    Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America 2002 May 14;99(10):6925-30
  18. Chu F, Borthakur A, Sun X, Barkinge J, Gudi R, Hawkins S, Prasad KV
    The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis. Apoptosis : an international journal on programmed cell death 2004 Jan;9(1):83-95