Elsevier

Progress in Neurobiology

Volume 67, Issue 3, 15 June 2002, Pages 203-233
Progress in Neurobiology

Neurotrophin signaling through the p75 neurotrophin receptor

https://doi.org/10.1016/S0301-0082(02)00016-3Get rights and content

Abstract

The neurotrophins are growth factors that play critical roles in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases and the p75 neurotrophin receptor (p75NTR). While the Trk receptors are responsible for most of the survival and growth properties of the neurotrophins, the actions of p75NTR fall into two categories. First, p75NTR is a Trk co-receptor that can enhance or suppress neurotrophin-mediated Trk receptor activity. Second, p75NTR autonomously activates signaling cascades that result in the induction of apoptosis or in the promotion of survival. The signaling cascades activated by p75NTR remain elusive, but structural and functional differences between p75NTR and other tumor necrosis factor receptor (TNFR) superfamily members suggest that p75NTR employs distinct signaling pathways. p75NTR has been shown to activate the NF-κB, Akt, and JNK pathways and interacts with several adaptor proteins. Of these, NRAGE, NADE, and NRIF have been associated with the induction of apoptosis, and FAP-1, RIP2, and TRAF6 appear to promote cellular survival. It remains a major challenge to link the various p75NTR binding proteins to specific p75NTR-dependent functions, but the identification of p75NTR interactors and signaling pathways has sparked new directions in p75NTR research, and will provide a better understanding of this enigmatic receptor.

Introduction

Development and maintenance of the nervous system is orchestrated by a complex interplay between diffusible cues and their corresponding cell surface receptors. The best characterized mammalian neuronal differentiation factors are the neurotrophins. The neurotrophins were initially identified as target-derived neuronal survival factors (Purves et al., 1988, Oppenheim, 1991) but are now recognized to mediate a wide range of responses that include the regulation of neuroblast and neural crest cell proliferation, regulation of neurite outgrowth, modulation of synaptic properties, maintenance of survival, and induction of apoptosis (Lewin and Barde, 1996, Bibel and Barde, 2000, Huang and Reichardt, 2001).

In addition to their normal physiological roles, neurotrophins have also been implicated in neurological disorders, including Alzheimer’s disease (Mufson et al., 1989, Phillips et al., 1991), Parkinson’s disease (Hyman et al., 1991), epilepsy (Gall and Isackson, 1989, Isackson et al., 1991), and cancers of the central nervous system (CNS) (Kogner et al., 1993, Segal et al., 1994, Ryden et al., 1996). It is likely that elucidation of the molecular mechanisms that control neurotrophin function will reveal targets for pharmacological intervention that will have substantial benefit in treating human nervous system disease.

The signal transduction systems that mediate the diverse biological functions of the neurotrophins are initiated through interactions with two categories of cell surface receptors, the tropomyosin-related kinase (Trk) tyrosine kinase receptors and the p75 neurotrophin receptor (p75NTR). These receptors share no sequence similarity in either ligand-binding or cytoplasmic domains, and activate distinct neurotrophin-dependent signaling pathways. In many instances, Trk and p75NTR not only activate autonomous pathways but also collaborate to mediate effects of the neurotrophins. In this review, the neurotrophins and their receptors will be discussed, with emphasis placed on the evidence supporting a role for p75NTR in the regulation of neurotrophin action.

Section snippets

The neurotrophins

Nerve growth factor (NGF), the prototypic neurotrophin, is the best characterized member of this family of growth factors that in mammals also includes brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 (Snider, 1994). With the exception of NT-4/5, which is not detected in avian species, the neurotrophin sequences are highly conserved in vertebrates. The nt-6 and nt-7 genes encode neurotrophins that have been identified only in fish, and do not appear to have mammalian

The Trk receptors

TrkA was originally characterized as a transforming oncogene in which tropomyosin was fused to an unknown tyrosine kinase (Martin-Zanca et al., 1989). The corresponding proto-oncogene was shown to be a member of a highly related family of transmembrane tyrosine kinases which were expressed in discrete neuronal populations and which bound and were activated by specific neurotrophins, with TrkA preferentially binding NGF, TrkB preferring BDNF and NT-4/5, and TrkC interacting with NT-3 (Klein et

The p75 neurotrophin receptor

Binding studies on PC12 cells and primary peripheral neurons established that NGF responsive cells had high and low affinity binding sites, with dissociation constants (Kd) of ∼10−11 and ∼10−9 M, respectively (see discussion in Section 5.2). When p75NTR was cloned (Chao et al., 1986, Johnson et al., 1986, Radeke et al., 1987), transfection studies revealed that p75NTR bound NGF at the lower of these affinities and the receptor was therefore termed the low affinity NGF receptor. With the

Functional aspects of p75NTR

Assigning physiological functions to p75NTR and elucidating its signaling mechanisms have proven challenging. Nonetheless, present data suggest that p75NTR has two main physiological functions: modulating Trk receptor signaling and initiating autonomous signaling cascades that regulate survival and apoptosis.

Future directions

p75NTR is an unusual member of the TNF receptor superfamily that acts as both a Trk co-receptor and as an autonomous signaling unit. It can both enhance or suppress neurotrophin-dependent Trk activation and its reported autonomous signaling activities run the gamut from enhancing survival to inducing apoptosis, and from facilitating cell migration to inhibiting neurite growth. However, despite this plethora of intriguing findings, their physiological significance is uncertain in the absence of

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    Present address: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

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