P75(NTR) AND THE CONCEPT OF CELLULAR-DEPENDENCE - SEEING HOW THE OTHER HALF DIE

Cells depend on specific stimuli, such as trophic factors, for surviva l and in the absence of such stimuli, undergo apoptosis. How do cells initiate apoptosis in response to the withdrawal of trophic factors or other dependent stimuli? Recent studies of apoptosis induction by neu rotrophin withdrawal argue for a novel form of pro-apoptotic signal tr ansduction - 'negative signal transduction' - in which the absence of ligand-receptor interaction induces cell death. We have found that the prototype for this form of signaling - the common neurotrophin recept or, p75(NTR) - creates a state of cellular dependence (or addiction) o n neurotrophins, and that this effect requires an 'addiction/dependenc e domain' (ADD) in the intracytoplasmic region of p75(NTR). We, have r ecently found other receptors that include dependence domains, arguing that dependence receptors, and their associated dependence domains, m ay be involved in a rather general mechanism to create cellular states of dependence on trophic factors, cytokines, adhesion, electrical act ivity and other dependent stimuli.