p75NTR and the concept of cellular dependence: seeing how the other half die

Abstract

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, p75 NTR ± 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 p75 NTR . 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.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Two notable exceptions are p75 NTR and UNC5H receptors: in those two cases, two regions corresponding to known functional domains are responsible for apoptosis induction. The first region is their death domain, which is structurally related to the death domain of receptors of the TNF receptor superfamily (Hofmann and Tschopp, 1995;Bredesen et al, 1998;Llambi et al, 2001). The second region is the chopper domain for p75 NTR (Coulson et al, 2000) and the ZU5 domain for UNC5H (Williams et al, 2003).…”

Receptors that mediate cellular dependence

“…Other cells may undergo PCD following the withdrawal of trophic factors (e.g., the neurotrophins), cytokines, hormonal support, electrical activity, or other stimuli. 2 Depending on the cell type and its state of differentiation, cells require different supportive stimuli for survival. For example, prostate epithelial cells may require testosterone for survival, and for such cells the withdrawal of testosterone leads to apoptosis.…”

“…In this latter case, ligand binding blocks the proapoptotic effect of the fragments, at least in some cases by inhibiting the proteolytic processing of the receptor. 2,10 This form of signal transduction has been dubbed negative signal transduction. 2 Cellular dependence on trophic influences for their antiapoptotic effect is mediated, at least in part, by specific 'dependence receptors' or 'addiction receptors.'…”

“…2,10 This form of signal transduction has been dubbed negative signal transduction. 2 Cellular dependence on trophic influences for their antiapoptotic effect is mediated, at least in part, by specific 'dependence receptors' or 'addiction receptors.' These receptors induce apoptosis in the absence of the required stimulus (when unoccupied by a trophic ligand, or possibly when bound by a competing 'antitrophin'), but block apoptosis following binding of their respective ligands.…”

Neurotrophins and B-cell malignancies

“…It utilizes the 'addiction/dependence domain' described by Dale Bredesen [89], and later identified as the 'Chopper' domain [90], rather than the death domain (DD) which binds to adaptors on ligand binding. Furthermore, p75 NTR is known to enhance ligand binding to the Trk receptors, increasing their affinity for neurotrophins by 10-fold [91].…”