Cells depend on specific stimuli, such as trophic factors, for survival 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 neurotrophin withdrawal argue for a novel form of pro-apoptotic signal transduction - '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 receptor, p75NTR - creates a state of cellular dependence (or addiction) on neurotrophins, and that this effect requires an 'addiction/dependence domain' (ADD) in the intracytoplasmic region of p75NTR. We have recently found other receptors that include dependence domains, arguing that dependence receptors, and their associated dependence domains, may be involved in a rather general mechanism to create cellular states of dependence on trophic factors, cytokines, adhesion, electrical activity and other dependent stimuli.
A possible link has been found between beta-amyloid peptide toxicity and preferential degeneration of cells expressing the nerve growth factor receptor, p75-NGFR. Beta-amyloid peptide has been ...implicated in the pathogenesis of Alzheimer's disease.
The tumor necrosis factor receptor superfamily includes twelve members, at least two of which--tumor necrosis factor receptor I and FAS/Apo-1--induce cell death following ligand binding. This review ...summarizes data suggesting that two other members of the family--p75NGFR and CD40--achieve a similar effect in the inverse fashion; they induce apoptosis constitutively when unbound by their respective ligands, with the induction of apoptosis being inhibited by the binding of their respective ligands. The potential roles that such receptors may play in development and pathological processes are discussed.
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