Apoptosis initiation through the cell-extrinsic pathway

Apoptosis is a tightly regulated cell suicide process used by metazoans to eliminate unwanted or damaged cells that pose a threat to the organism. Caspases-specialized proteolytic enzymes that are responsible for apoptosis initiation and execution-can be activated through two signaling mechanisms: (1) the cell-intrinsic pathway, consisting of Bcl-2 family proteins and initiated by internal sensors for severe cell distress and (2) the cell-extrinsic pathway, triggered by extracellular ligands through cognate death receptors at the surface of target cells. Proapoptotic ligands are often expressed on the surface of cytotoxic cells, for example, certain types of activated immune cells. Alternatively, these ligands can function in shed, soluble form. The mode of ligand presentation can substantially alter the cell response to receptor stimulation. Once receptor ligation on the target cell occurs, a number of intracellular signaling cascades may be initiated. These can lead to a variety of cellular outcomes, including caspase-mediated apoptosis, a distinct type of regulated cell death called necroptosis, or antiapoptotic or inflammatory responses. Death receptor signaling is kept tightly in check and plays critical homeostatic roles during embryonic development and throughout life.