Fig. 4. Mechanisms for integrins to influence DR-mediated apoptosis. The induction of apoptosis by DRs is triggered by ligand-induced clustering, leading to the recruitment of FADD and subsequently initiator caspases such as caspase 8 or 10 via their DED domains (banana shape) to form a DISC (death-inducing signal complex). Caspases autoactivate and form dimers, leaving the DED domains at the DISC, and go on to cleave downstream targets, such as Bid (which will activate the intrinsic apoptosis pathway) and the executioner caspases. The formation of the DISC is influenced by both the presence of DED-containing inhibitory proteins, such as FLIPs, and protein kinase C activity. Activated PKC blocks recruitment and/or activation of caspase 8 at the DISC and is permissive for the assembly of signaling downstream of cFLIP via the Raf-MEK-ERK pathway or through Traf to JNK (not shown). Integrin ligation leads to signaling via the ERK pathway (as described in Fig. 3) as well as to NFB translocation to the nucleus, which together promote the transcription of anti-apoptotic proteins such as the IAPs and cFLIP. Erk activation of Rsk also leads to phosphorylation of the transcription factor CEBP, creating an XEXD motif that blocks caspase 8 activity.