Trends in Neurosciences
Volume 20, Issue 7, 1 July 1997, Pages 287-291
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p75NTR and apoptosis: Trk-dependent and Trk-independent effects

https://doi.org/10.1016/S0166-2236(96)01049-1Get rights and content

Abstract

The ongoing dissection of the roles of p75NTR and TrkA, -B and -C in neurotrophin signaling has generated a number of apparent paradoxes. Limiting consideration to the role of p75NTR in cell death, a theory is proposed that is based on the following postulates: (1) that p75NTR displays a pro-apoptotic intrinsic (ligand-independent, Trk-independent) receptor effect (IRE), which is inhibited by ligand binding; (2) that p75NTR and TrkA exhibit mutual repression of signaling; and (3) that p75NTR and TrkA are required for the efficient generation of high-affinity NGF binding sites.

Section snippets

Intrinsic receptor effect (IRE) vs ligand-dependent receptor effect (LiRE)

Receptor effects that do not require ligand binding have been described previously: for example, the sky oncogene product[25]functions as a tyrosine kinase in the absence of ligand binding. Perhaps a more appropriately physiological example is that of CD45, which apparently functions as a phosphatase in its monomeric form, but suppresses this activity following dimerization[26].

In general, receptor effects have been defined by comparing the cellular status in the presence and absence of the

p75NTR and Trk: mutual repression?

Over the past few years, several reports have appeared describing interactive effects of p75NTR and TrkA. Taken together, these reports argue for the possibility that p75NTR and TrkA exhibit mutual repression: with coexpression, signaling through one is inhibited by the presence of the other, such that a maximal signal is obtained only by costimulation, which relieves the mutual repression (Fig. 2). Such a proposed relationship would have striking effects on specificity and on signal-to-noise

p75NTR-mediated apoptosis: ligand-dependent, ligand-independent or both?

Several groups have now reported that p75NTR mediates apoptosis, and, interestingly, both ligand-dependent19, 20and ligand-independent7, 21, 23, 36apoptosis induction have been described. The ligand-independent apoptosis induction can occur in cells that do or do not express Trk[21]. As noted above, earlier work from von Bartheld et al.[8]demonstrated enhanced neural cell death in the presence of NGF, in cells that expressed TrkB but not TrkA. Whether mismatched Trk family members are expressed

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