Neurotrophins are a family of protein nerve growth factors that are critical for the development and functioning of the nervous system, regulating a wide range of biological processes: neuronal survival, proliferation, cell migration, axonal and dendritic outgrowth and patterning, synapse strength and plasticity, injury protection, as well as controlling the activity of ion channels and neurotransmitter receptors. Besides their diverse roles in the nervous system, they are also involved in vascular and tumour biology. Several neurotrophins have been identified, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), NT4, NT5, and NT7. Neurotrophins exert their control through a variety of signalling cascades, which involve binding to two classes of cell surface receptors, the Trk receptor tyrosine kinase family and the structurally unrelated p75NTR (a member of the tumour necrosis factor receptor family) in order to modulate diverse and sometimes opposing biological actions.
Neurotrophins can promote both neuronal cell survival and death. Trk receptors are known to positively affect neuronal survival and differentiation through their activation of different signalling cascades, including the Ras/MAPK (mitogen-activated protein kinase) pathway and the PI3K (phosphatidylinositol 3-kinase) pathway, which act to intercept nuclear and mitochondrial cell-death programs.
The activation of the Ras/MAPK pathway is essential for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells. Several pathways can lead from Trk receptors to Ras activation, most involving the phosphorylation of tyrosine residues in the Trk receptors. The various MAPKs activated through Ras and Rap1 have different downstream targets that mediate gene transcription via activation of several different transcription factors resulting in diverse biological responses.
The recruitment of PI3K to activated Trk receptors is critical for receptor-mediated survival signalling via second messengers that activate the serine threonine kinase Akt (also known as protein kinase B). Substrates of Akt include proteins involved in several steps of cell death pathways (FKHRL1 forkhead transcription factor, Bad, Caspase-9, GSK3b, and NFkB), which can be intercepted by Akt.
In contrast, activation of the p75NTR receptor has been implicated in neuronal cell death through its activation of the JNK1 (c-Jun N-terminal kinase) pathway and the p53 pathway, as well as through the neurotrophin-receptor-interacting factor (NRIF). However, the opposite has also been found, where the p75NTR receptor has been shown to promote neuronal cell survival through its activation of the NF-kB transcription factor, following its interaction with NGF. p75NTR can also promote neurite outgrowth and cell migration. There is even some question as to whether Trk receptors can play a part in neuronal cell death. Therefore, neuronal cell fate seems to be a balancing act that is in part determined by the associated signalling molecules elicited upon activation of the receptor.
The Trk (tropomyocin receptor kinase) receptor was first identified as a colon-derived oncogene in which tropomyocin was fused to a tyrosine kinase domain. However, the normal cellular counterpart of this oncogene, namely Trk (lacking tropomyocin), was found to be a transmembrane protein that is highly expressed in the developing and adult nervous system. To date, three Trk receptors have been identified, TrkA (or NTRK1), TrkB (or NTRK2), and TrkC (or NTRK3), each of which has a different neurotrophin binding specificity: TrkA binds NGF, TrkB binds BDNF and NT4, and TrkC binds NT3 (TrkA and TrkB bind NT3 to a lesser extent). The neurotrophins are synthesised in a precursor form (pro-neurotrophins) that are proteolytically cleaved to generate mature neurotrophins. These pro-neurotrophins bind to p75NTR with a higher affinity than mature neurotrophins, but bind only weakly to Trk receptors. Therefore, p75NTR can bind all the neurotrophins in their precursor form, while the Trk receptors are selective for specific mature neurotrophins (see picture below).
Neurotrophins and their receptors. Unprocessed ligands bind with high affinity to p75NTR, while the processed ligands have a higher affinity for specific Trk receptors.
Reprinted from Annual Review of Neuroscience 26, R. A. Segal, Selectivity in Neurotrophin Signaling: Theme and Variations, PP. 299-330, 2003, PMID: 12598680