The hypothesis that the expression of p75NTR, the low affinity neurotrophin receptor, induces apoptosis which is inhibited by the binding of ligand, is put forth, and studies to explore the mechanism by which this may be achieved are proposed. New data have defined the requirement for a carboxyterminal death domain in the induction of apoptosis by p75NTR, TNFR I, and FAS. Deletion of this region in p75NTR results in conversion of the wild type, pro-apoptotic p75NTR to an anti-apoptotic mutant. Point mutants W359A and E348A abolish the apoptotic activity of p75NTR, just as corresponding mutations in TNFR I (W378A and E369A) abolish its activity as a pro-apoptotic receptor. These findings argue that p75NTR induces apoptosis by a mechanism that is biochemically similar to that of TNFR I. Because of recent findings of intracytoplasmic proteins with death domains that interact with TNFR I and FAS, a similar model is proposed for p75NTR, with the single difference being that the interacting protein is anti-apoptotic rather than pro-apoptotic. The proposal to evaluate this model includes (1) Mutagenesis studies, which will help to define the aminoterminal and carboxyterminal extents of the death domain; (2) Chimeric studies using EGFR-p75 and PDGFR-p75, which will help to determine the requirement for transmembrane and extracellular sequences of p75; and (3) 2-hybrid studies to identify proteins that interact with the intracytoplasmic domain of p75NTR. In sum, these studies should help to define the mechanism by which the expression of p75NTR leads to neural apoptosis.
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