Apoptosis and survival - Apoptotic TNF-family pathways

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 (GITRL)/ 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].

References:

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