Neurotrophins (NGF, BDNF, NTF3 and NTF4) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: NTRK (TRK) tyrosine kinase receptors (TRKA, TRKB, TRKC), which differ in their preferred neurotrophin ligand, and p75NTR death receptor, which interacts with all neurotrophins. Besides the nervous system, TRK receptors and p75NTR are expressed in a variety of other tissues. For review, please refer to Bibel and Barde 2000, Poo 2001, Lu et al. 2005, Skaper 2012, Park and Poo 2013.
NTRK receptors, NTRK1 (TRKA), NTRK2 (TRKB) and NTRK3 (TRKC) are receptor tyrosine kinases activated by ligand binding to their extracellular domain. Ligand binding induces receptor dimerization, followed by trans-autophosphorylation of dimerized receptors on conserved tyrosine residues in the cytoplasmic region. Phosphorylated tyrosines in the intracellular domain of the receptor serve as docking sites for adapter proteins, triggering downstream signaling cascades.
NTRK1 (TRKA) is the receptor for the nerve growth factor (NGF). NGF is primarily secreted by tissues that are innervated by sensory and sympathetic neurons. NTRK1 signaling promotes growth and survival of neurons during embryonic development and maintenance of neuronal cell integrity in adulthood (reviewed by Marlin and Li 2015).
Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NTF4, also known as NT-4) are two high affinity ligands for NTRK2 (TRKB). Neurotrophin-3 (NTF3, also known as NT-3) binds to NTRK2 with low affinity and may not be a physiologically relevant ligand. Nerve growth factor (NGF), a high affinity ligand for NTRK1, does not interact with NTRK2. NTRK2 signaling is implicated in neuronal development in both the peripheral (PNS) and central nervous system (CNS) and may play a role in long-term potentiation (LTP) and learning (reviewed by Minichiello 2009). NTRK2 may modify neuronal excitability and synaptic transmission by directly phosphorylating voltage gated channels (Rogalski et al. 2000).
NTF3 (NT-3) is the ligand for NTRK3 (TRKC). Signaling downstream of activated NTRK3, regulates cell survival, proliferation and motility. In the absence of its ligand, NTRK3 functions as a dependence receptor and triggers BAX and CASP9-dependent cell death (Tauszig-Delamasure et al. 2007, Ichim et al. 2013).