NTRK2 (TRKB) belongs to the family of neurotrophin tyrosine kinase receptors, also known as NTRKs or TRKs. Besides NTRK2, the family includes NTRK1 (TRKA) and NTRK3 (TRKC). Similar to other receptor tyrosine kinases (RTKs), NTRK2 is activated by ligand binding to its 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 cascaded. Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NTF4, also known as NT-4) are two high affinity ligands for NTRK2. Neurotrophin-3 (NTF3, also known as NT-3), a high affinity ligand for NTRK3, binds to NTRK2 with low affinity and it is not clear if it the low level of activation of NTRK2 by NTF3 plays a physiologically relevant role. Nerve growth factor (NGF), a high affinity ligand for NTRK1, does not interact with NTRK2. NTRK2 activation triggers downstream RAS, PI3K, and PLCgamma signaling cascades, thought to be involved in neuronal development in both the peripheral (PNS) and central nervous system (CNS). In addition, NTRK2 plays an important, but poorly elucidated, 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).
It was recently demonstrated that the protein tyrosine phosphatase PTPN12 negatively regulates NTRK2 signaling and neurite outgrowth. In the presence of PTPN12, NTRK2 phosphorylation at tyrosine Y816 decreases. It has not yet been demonstrated that PTPN12 acts directly to dephosphorylate Y816 (and possibly other phosphotyrosines) of NTRK2 (Ambjorn et al. 2013).
Binding of SH2D1A (SAP) to NTRK2 attenuates NTRK2 trans autophosphorylation and downstream signaling through an unknown mechanism (Lo et al. 2005).
Little is known about downregulation of NTRK2 (TRKB) receptor via ubiquitin dependent pathways (Sanchez Sanchez and Arevalo 2017). CBL, a ubiquitin ligase involved in degradation of many receptor tyrosine kinases, was shown to ubiquitinate and, unexpectedly, increase stability of NTRK2 (Pandya et al. 2014). NTRK2 undergoes ubiquitination by the TRAF6 E3 ubiquitin ligase complex. While ubiquitination by the TRAF6 complex negatively regulates NTRK2 induced AKT activation, the effect of TRAF6 mediated ubiquitination on NTRK2 protein levels has not been examined (Jadhav et al. 2008).
Downregulation of the TRKB receptor may depend on the activating ligand, with BDNF inducing more rapid ubiquitination and degradation compared to NTF4 (NT 4). NTRK2 undergoes both lysosome dependent and proteasome dependent degradation upon stimulation by BDNF, while stimulation by NTF4 may protect NTRK2 from the lysosome degradation route (Proenca et al. 2016).