The death receptor pathway

The TNF receptor superfamily is a large group of membrane-associated receptors characterized by structural similarities in their extracellular and intracellular domains. A subgroup of these receptors, the so-called death receptors, shares an intracellular motif termed the death domain. When engaged by their cognate ligands, these receptors trigger an apoptotic pathway often referred to as the extrinsic pathway. This is mediated by the recruitment of various adaptor proteins, which, in turn, recruit and facilitate the activation of initiator caspases, initiating a proteolytic cascade. Death receptor deregulation has been associated with several pathological conditions; for this reason, death receptors have been the subject of intensive studies. These studies have also revealed, in different settings, that death receptors have additional apoptosis-independent functions, including regulation of cell proliferation and differentiation, chemokine production, and tumor-promoting activity. This chapter provides an updated overview on the signaling pathways mediated by the death receptors and on their role in human physiology and pathophysiology.