Differential Modulation of Neuron Survival during Development by Nerve Growth Factor Binding to the p75 Neurotrophin Receptor

Abstract

Nerve growth factor (NGF) supports the survival and differentiation of distinct populations of peripheral and central neurons. NGF binds to two classes of cell-surface receptors, the protein tyrosine kinase TrkA and the smaller p75 receptor lacking intrinsic catalytic activity. It has been suggested that both receptors are required for NGF high affinity binding, although TrkA appears to be sufficient for transducing most of the biological effects of NGF. Some evidence suggests that p75 could play a modulatory role on TrkA activation by an as yet unknown mechanism. In this study, we have investigated functional roles of p75 using a purified triple mutant NGF (triNGF) deficient in p75 binding but retaining significant TrkA binding and activation. The mutant was found to be as potent as wild type NGF at promoting survival of serum-deprived TrkA-expressing fibroblasts. On developing chick sensory neurons, survival responses to mutant and native NGF were indistinguishable when assayed at nanomolar concentrations. However, triNGF was 3-to 4-fold less potent than wild type NGF at lower concentrations (i.e. 10 ؊11 M). Interestingly, in PC12 cells coexpressing TrkA and p75, no high affinity binding sites for triNGF could be detected. The reduced responsiveness to triNGF in sensory neurons was increasingly evident at later developmental stages; late embryonic neurons did not respond at all to concentrations of triNGF that were saturating at earlier developmental stages. Likewise, although no difference could be seen between wild type and mutant NGF on the survival responses of embryonic rat superior cervical ganglion sympathetic neurons, the mutant was much less potent than native NGF on postnatal sympathetic neurons. In sensory neurons, the decrease in responsiveness to triNGF correlated with a developmental reduction in the expression of both p75 and TrkA. Thus, NGF binding to p75 enhances responsiveness to ligand, particularly when this is present at limiting concentrations. During development, p75 modulates responsiveness to NGF so that binding to p75 becomes increasingly important in neurons undergoing a down-regulation of NGF receptors. These results support a ligand-dependent modulatory role for p75 in NGF-mediated neuron survival consistent with p75 functioning as a TrkA regulator and/or signaling receptor.

An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function

“…NTR -TrkA heterodimer model is not supported by structural data (15)(16)(17), and the ligand passing model, although consistent with the finding that a NGF mutant that cannot bind p75 NTR has only low binding affinity (18), is inconsistent with the observation that the extracellular ligand-binding domain of p75 NTR is not required to create high-affinity NGF binding sites (19,20). Therefore, although a heteroreceptor complex may form, and ligand transfer from p75 NTR to TrkA could occur, these mechanisms cannot be the sole basis for the formation of high-affinity binding sites.…”

Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism

“…Wild type NGF (binds TrkA and p75 NTR ) serves as an internal control. NGF-KKE mutant (herein termed NGF-C) is a selective TrkA agonist (21,22). The NGF-Delta 9/13 mutant (herein termed NGF-A) is a selective p75 NTR agonist (23).…”

Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin

“…p75 NTR is a membrane glycoprotein that binds all neurotrophins identified to date, but its biological role in mediating the effects of this family of growth factors is not well defined. In addition to forming a high-affinity binding site when coexpressed with trk receptors (Barker and Shooter, 1994;Verdi et al, 1994;Ryden et al, 1997;Bibel et al, 1999), recent evidence has suggested that p75 NTR may also act autonomously to activate signaling cascades involved in apoptosis, mediated either through the generation of ceramide by sphingomyelin hydrolysis or through Traf6 (Dobrowsky et al, 1994;Dobrowsky et al, 1995;Khursigara et al, 1999). Other studies have shown that activation of p75 NTR by nerve growth factor (NGF) causes the translocation of NF-kB to the nucleus and promotes cell survival (Carter et al, 1996;Bhakar et al, 1999).…”