p75NTR – live or let die
Introduction
Sculpting of the vertebrate nervous system crucially depends on tightly regulated survival and death signals. Trophic stimuli ensure survival of preferred developing neurons, whereas apoptotic signals function to match the number of neurons to the target size and to refine target innervation. The closely related mammalian neurotrophins (NTs) nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3 and NT4 are essential for this developmental process as they regulate growth, differentiation and death of neurons [1]. Bioactive NTs are homodimers that target two classes of transmembrane receptors, the receptor tyrosine kinases (Trk)-A, -B, and -C, and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor superfamily [1, 2]. Whereas p75NTR binds all NTs equally well, TrkA preferentially interacts with NGF, TrkB with BDNF and NT4, and TrkC with NT3. Each NT dimer can simultaneously engage two Trk receptors in a high-affinity complex that mediates receptor transphosphorylation and activation of well defined signaling pathways (Figure 1; [2]). Ultimately, Trk stimulates neuronal survival, differentiation, neurite outgrowth and myelination, in addition to synaptic plasticity and function. Here, we review the role of p75NTR as a facilitator of Trk-mediated neuronal survival and as a regulator of neuronal cell death, and we put forward the hypothesis that these opposing roles are dictated by distinct partnering molecules. Other functions of p75NTR have recently been reviewed elsewhere [1, 3].
Section snippets
p75NTR is a positive modulator of Trk-mediated survival functions
The extracellular domain of the common receptor p75NTR comprises four tandemly arranged cysteine-rich domains required for NT binding. Although it is known as the low-affinity receptor, p75NTR actually binds NTs with about the same affinity as monomeric Trk [1]. However, recent structural analysis of p75NTR with NGF suggests the formation of an asymmetric complex of one dimeric NT bound to a single p75NTR. Thus, the conformation of the p75NTR–NT complex is not able to recruit more than one
p75NTR is a proapoptotic receptor in the absence of Trk
In addition to modulating Trk-mediated functions, p75NTR also controls and conveys Trk-independent activities. Numerous studies have demonstrated that p75NTR, depending on the cellular context, can activate signaling cascades regulating apoptosis, Schwann cell migration, myelination, axonal growth and regeneration [1]. Indeed, the p75NTR cytoplasmic tail contains several potential motifs for interactions with downstream signaling molecules, and similar to other members of the TNF receptor
p75NTR employs multiple signaling pathways to signal cell death
The signaling pathways underlying the p75NTR-dependent apoptotic response are incompletely understood but are believed to involve the activation of JNK (Figure 2). Further downstream events include phosphorylation of c-jun, activation of both p53 and the ‘BH3-domain only’ family members Bad and Bim, mitochondrial translocation of Bax and release of mitochondrial cytochrome c and activation of caspases 9, 6 and 3 [3, 13, 14, 15, 16].
Proximal events that couple p75NTR to JNK are less clear but
The cytoplasmic tail of p75NTR is subject to proteolytic processing
p75NTR undergoes α-secretase- and TNF-α convertase (TACE)-dependent ectodomain shedding (Figure 2; [21]). Cleavage abolishes ligand-mediated signaling but the membrane-tethered carboxyl-terminal fragment is still able to refine Trk-mediated trophic activities [22•, 23•]. Ectodomain shedding might have several functions. It might serve to generate soluble decoy receptors that scavenge NTs in the extracellular space but, given the right setting, it might also facilitate rather than impede p75NTR
s-p75NTR; a redundant receptor variant?
Although ectodomain shedding of p75NTR constitutes a poorly understood mechanism, the recent recognition of a short p75NTR splice variant (s-p75NTR) lacking the NT binding domain supports the hypothesis that fragments of p75NTR partake in apoptotic signaling (Figure 2).
s-p75NTR arises from alternative splicing of exon III of the p75NTR locus. This variant, which is expressed in several neuronal tissues, is unable to bind NTs [25]. As a consequence of alternative splicing, p75NTR/exonIII
Proneurotrophins: the death signal
NTs are synthesized as precursors. The pro-NTs are processed in the trans-Golgi network by pro-protein convertases to liberate the biologically active carboxyl-terminal fragment from the amino-terminal pro-domain [28]. The amino-terminal pro-domain assists in folding and secretion of the mature NT, as exemplified by a polymorphism in the BDNF gene leading to a valine–methionine substitution at position 66 in the pro-domain [29•]. Carriers, heterozygous for this polymorphism, suffer from
Sortilin: a deadly consort
The ability of proNGF to activate p75NTR over TrkA was initially believed to reflect differences in affinity for the two receptors [31]. However, proNGF binds equally well to p75NTR and TrkA but with a tenfold lower affinity than NGF, reflecting that p75NTR does not alone account for cellular binding [33••]. The authentic proNGF receptor was subsequently identified as Sortilin, a ∼95 kDa member of the recently discovered family of Vps10p-domain receptors. In vertebrates, this family comprises
p75NTR death signals in neuronal diseases
p75NTR is abundantly expressed during development but is downregulated in the adult organism. Yet, p75NTR is re-expressed in conditions of increased neuronal cell death including mechanical damage, focal ischemia, axotomy, stroke and Alzheimer's disease (AD), suggesting a physiological role during neuronal degeneration [43]. For example, in a mouse model of amyotroph lateral sclerosis, p75NTR expression is upregulated in dying motor neurons, and disease onset is delayed on the p75NTR/exonIII
Conclusions
After a long time in the shadow of Trks, p75NTR is now emerging as a key player in a growing network of interacting molecules that prime neuronal cells for life or death. It is still premature to draw any conclusions regarding the significance of p75NTR cleavage products but at least two scenarios involving the full-length receptor can be envisioned: one in which p75NTR collaborates with Trks and mature NTs to promote life, and one in which it engages proNGF and Sortilin to induce cell death.
Update
A recent paper by Pang et al. [57] demonstrates that proBDNF, similar to proNGF, is also secreted in vivo and is a potent inducer of p75NTR-mediated apoptosis. The authors also show that cleavage of proBDNF to mature BDNF by tissue plasminogen activator (tPA) regulates late-phase long-term potentiation (L-LTP) and memory, suggesting that proneurotrophins in general might be important participants in diverse extracellular functions.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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