TNF-R2, CD40L(TNFSF5), BAFF(TNFSF13B), NGFR(TNFRSF16), Sequestosome 1(p62), PKC-zeta, OX40L(TNFSF4), TNF-alpha, NIK(MAP3K14), IKK-gamma, Bcl-XL, IKK (cat), RIPK1, RANKL(TNFSF11), TRAF3, BFL1, TRAF2, TACI(TNFRSF13B), OX40(TNFRSF4), CD40(TNFRSF5), TRADD, TRAF6, RelB (NF-kB subunit), APRIL(TNFSF13), IKK-alpha, TNF-R1, NF-kB, IRAK1/2, TWEAK(TNFSF12), FN14(TNFRSF12A), RANK(TNFRSF11A), IKK-beta, TRAF5, BCMA(TNFRSF17), NGF, NF-kB p52/RelB, RelA (p65 NF-kB subunit), Bcl-2, NF-kB2 (p100), I-kB, NF-kB2 (p52)
Anti-apoptotic TNFs/NF-kB/Bcl-2 pathway
The members of the tumour necrosis factor ligand family (TNFs) may induce both apoptotic and anti-apoptotic pathways. TNFs transduces cellular responses through activation of different TNF-receptors (TNFRs).
One important mechanism of cell survival is the activation of transcription of different anti-apoptotic proteins by TNFs via the nuclear factors of kappa light polypeptide in B-cells ( NF-kB ) signaling cascade .
Some TNFs/TNFRs may activate expressions of anti-apoptotic members of the Bcl-2 family. For example, expression of B-cell CLL/lymphoma 2 ( Bcl-2 ), BCL2-like 1 ( Bcl-XL ) and/or BCL2-related protein A1 ( BFL1 ) may be stimulated by:
. tumor necrosis factor, member 2 ( TNF-alpha )/ tumor necrosis factor receptor superfamily, member 1A ( TNF-R1 ) and TNF-alpha/ tumor necrosis factor receptor superfamily, member 1B ( TNF-R2 ) , ;
. tumor necrosis factor (ligand) superfamily, 4 member ( OX40L )/ tumor necrosis factor receptor superfamily, member 4 ( OX40 ) ;
. tumor necrosis factor (ligand) superfamily, member 5 ( CD40L )/ tumor necrosis factor receptor superfamily, member 4 ( CD40 ) ;
. tumor necrosis factor (ligand) superfamily, member 12 ( TWEAK )/ tumor necrosis factor receptor superfamily, member 12A ( FN14 ) ;
. tumor necrosis factor (ligand) superfamily, member 13b ( BAFF )/ tumor necrosis factor receptor superfamily, member 13B ( TACI ), tumor necrosis factor (ligand) superfamily, member 13 ( APRIL )/ TACI, BAFF/ tumor necrosis factor receptor superfamily, member 17 ( BCMA ) and APRIL/ BCMA ;
. nerve growth factor, beta polypeptide ( NGF )/ tumor necrosis factor receptor superfamily, member 16 ( NGFR ) .
TNFRs transduces cellular responses via activation of different TNFR -associated factors (TRAFs). These are TRAF2, TRAF5 and TRAF6, mainly. TRAF3 serves as a negative regulator of the NF-kappaB pathway for many TNFRs , , .
Further, activation and nuclear translocation of NF-kB proteins can occur after the ligation of the cell-surface TNFRs by one of two pathways (canonical and non-canonical).
In a canonical pathways, TRAF2 activates the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma ( IKK gamma )/ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase alpha (IKK alpha )/ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta ( IKK beta ) complex, which subsequently phosphorylates NF-kB inhibitor ( I-kB ). Phosphorylation of I-kB leads to it ubiquitination and degradation within the 26S proteasome. Degradation of I-kB liberates different NF-kB transfactors, allowing its rapid translocation from the cytoplasm into the nucleus where it triggers the transcription of target genes .
In addition, the signal from TNF-R1 may be mediated via TNFR1-associated death domain protein ( TRADD )/ receptor TNFR-interacting serine-threonine kinase 1 ( RIPK1 ) pathway . The signal from NGFR may be mediated via the interleukin-1 receptor-associated kinase 1 and 2 ( IRAK1/2 )/ TRAF6/ sequestosome 1 ( p62 )/ protein kinase C, zeta ( PKC-zeta ) pathway .
In the non-canonical pathway, TRAFs stimulate NIK kinase, which subsequently activates IKK alpha by phosphorylation. IKK alpha promotes the processing of NF-kB2 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 of IKK beta and IKK gamma .
In addition, the TNF-R1/ TNF-R2 signal may be mediated via NIK/ IKK/ v-rel reticuloendotheliosis viral oncogene homolog A ( RelA ) .