The two signaling pathways that trigger apoptotic cell death are the intrinsic and extrinsic pathways. The extrinsic pathway refers to the death receptor mediated pathway and the intrinsic pathway is a mitochondrial mediated pathway. The extrinsic pathway starts outside a cell when circumstances in the environment determine that a cell must die. The pathway initiates apoptosis by a death ligand binding to a death receptor (e.g. TNFR1). The TNFR family includes 29 transmembrane receptor proteins, which are organized in homotrimers and activated by the binding of the corresponding ligand. Intrinsic pathways begin when an injury happens within the cell. For example, stresses like DNA damage, hypoxia, and oncogenes can activate intrinsic apoptotic pathways. The formation of the apoptosome or DISC activates initiator and common effector caspases that carry out the process of apoptosis. p53 detects cellular stress and is a crucial activator of the intrinsic pathway.
There is also an additional pathway that involves T-cell mediated cytotoxicity and performing-granzyme-dependent neutralization of the cell. The perforin/granzyme pathway can induce apoptosis via granzyme A or granzyme B. It is important to note that the intrinsic, extrinsic, and granzyme B pathways all lead towards the same terminal or execution pathway.