Neurotrophin-regulated signalling pathways

Abstract

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

Figure 1

Neurotrophin–receptor interactions. This illustrates the major interactions of each of the four mammalian neurotrophins. Each proneurotrophin binds p75NTR, but not the Trk receptors. Following maturation through proteolysis of the proneurotrophins, each mature neurotrophin is able to bind and activate p75NTR, but exhibits more specific interactions with the three Trk receptors. NGF binds specifically TrkA; BDNF and NT4 recognize TrkB; NT3 activates TrkC. In some cellular contexts, NT3 is also able to activate TrkA and TrkB with less efficiency. For simplicity, only the major tyrosine kinase-containing isoforms of the Trk receptors are depicted. Differential splicing generates isoforms of TrkB and TrkC that have truncated cytoplasmic domains lacking a tyrosine kinase motif. Splicing also generates an isoform of TrkC with a small insert in the kinase domain that affects substrate specificity. Splicing of exons that generate the extracellular domain of each Trk receptor results in the expression of receptors with small peptide inserts between the second immunoglobin and transmembrane domains that affect ligand-binding specificity. Ligand-binding specificity is also affected by the presence of p75NTR. Additional details are provided in the text.

Figure 2

Neurotrophin signalling. This depicts the interactions of each neurotrophin with Trk and p75NTR receptors and major intracellular signalling pathways activated through each receptor. The p75NTR receptor regulates three major signalling pathways. NF-κB activation results in transcription of multiple genes, including several that promote neuronal survival. Activation of the Jun kinase pathway similarly controls activation of several genes, some of which promote neuronal apoptosis. Ligand engagement of p75NTR also regulates the activity of Rho, which controls growth cone motility. Pro-apoptosis actions of p75NTR appear to require the presence of sortilin, which functions as a co-receptor for the neurotrophins. Sortilin is not depicted in this figure, but is described in the text. Each Trk receptor also controls three major signalling pathways. Activation of Ras results in activation of the MAP kinase-signalling cascade, which promotes neuronal differentiation including neurite outgrowth. Activation of PI3 kinase through Ras or Gab1 promotes survival and growth of neurons and other cells. Activation of PLC-γ1 results in activation of Ca²⁺- and protein kinase C-regulated pathways that promote synaptic plasticity. Each of these signalling pathways also regulates gene transcription. Many additional adaptors for p75NTR and Trk receptors have been identified which are not depicted in this figure for simplicity, but are described in more detail in the text. Interactions between p75NTR and Trk receptors are not depicted in this figure, but are described in the text. p75NTR also appears to function as constituent of other receptor complexes, most notably the Nogo receptor complex. These interactions and signalling pathways are not depicted here.