TRAIL signalling: decisions between life and death.

The TNF-related apoptosis-inducing ligand, TRAIL, has been shown to selectively kill tumour cells. This property has made TRAIL and agonistic antibodies against its death inducing receptors (TRAIL-R1 and TRAIL-R2) to some of the most promising novel biotherapeutic agents for cancer therapy. Here we review the signalling pathways initiated by the apoptosis- as well as the non-apoptosis-inducing receptors, TRAIL-R3 and TRAIL-R4. The TRAIL "death-inducing signalling complex" (DISC) transmits the apoptotic signal. DISC formation leads to activation of a protease cascade, finally resulting in cell death. The TRAIL death receptor-mediated "extrinsic" pathway and the "intrinsic" pathway, which is controlled by the interaction of members of the Bcl-2 family, interact with each other in the decision about life or death of a cell. Apoptotic and non-apoptotic signalling is influenced by the NF-kappaB, PKB/Akt and the MAPK signalling pathways. In this review we intend to summarise the most important findings on the TRAIL signalling network and the interplay in the decisions between life and death of a tumor cell.