Formation of the NFB-stimulating TNFR1 signaling complex. The classical NFB pathway is activated by a broad range of stimuli, including TNF-. Binding of TNF- to TNFR1 triggers recruitment of the death domain-containing proteins RIP1 and TRADD. Next, complex TRAF2-cIAP1/2 is recruited to TNFR1-bound TRADD. Recruitment of IKK2 subunit to TRADD-bound TRAF2 stimulates kinase activity of the IKK complex, following by proteolytic degradation of IB proteins. p65/p50 complex (NFB) is translocated to the nucleus to activate transcription of target genes. Alternative NFB pathway (not shown) is activated by a limited subgroup of TNF ligands and involves activation of NIK-mediated stimulation of IKK1 and conversion of p100-containing NFB complexes into p52-containing NFB complexes by proteolytic processing of p100 to p52. In addition, in TNF-mediated apoptosis, receptor aggregation results in recruitment of the adaptor protein Fas-associated death domain (FADD/MORT1) and caspase-8. Caspase-8 becomes activated and initiates apoptosis by direct cleavage of downstream effector caspases. The mitochondrial pathway is initiated by the release of apoptogenic factors such as cytochrome c, or Smac from mitochondria into the cytosol, which trigger caspase-3 activation through the formation of the cytochrome c/Apaf-1/caspase-9-containing apoptosome complex.
