It has been known for over half a century that cells depend on external signals for their survival which is then mediated by various transmembrane receptors and sensors. For example, cells may require specific soluble trophic factors, cytokines, hormones, extracellular matrix interactions, cell-cell interactions, or electrical activity for survival. For any given required stimulus, withdrawal leads to programmed cell death (or apoptosis). It has generally been assumed that apoptosis induced by withdrawal of supporting factors is due to the loss of the associated positive survival signals. While such survival signals are clearly very important, data obtained over the past 20 years argue for a complementary form of signal transduction that actively induces cell death following stimulus withdrawal.
This “negative signal transduction” is mediated by specific “dependence receptors (DRs)” that induce apoptosis in the absence of the required stimulus (e.g., when unbound by a trophic ligand). Thus, the presence of various dependence receptors at the surface of the cells creates a state of dependence (or addiction) to their respective ligands.