Neurotrophic receptor tyrosine kinase 2 (TrkB) (NTRK2)

Neurotrophic receptor tyrosine kinase 2 (TrkB) is a high-affinity cell surface receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) [1]. It is a member of the receptor tyrosine kinase family and is primarily expressed in the central and peripheral nervous systems, where it plays a fundamental role in neuronal survival, axonal growth, and synaptic plasticity [2]. The full-length isoform (TrkB-FL) contains an intracellular tyrosine kinase domain essential for mediating these neurotrophic effects through downstream signaling cascades like PI3K and MAPK [1, 2]. Dysregulation of TrkB signaling is implicated in various pathologies; reduced activity is associated with neurodegenerative diseases such as Alzheimer's and psychiatric conditions like major depressive disorder [2, 4]. Conversely, oncogenic activation through NTRK2 gene fusions or overexpression is a driver in several cancers, including neuroblastoma and certain lung adenocarcinomas [3]. Consequently, TrkB is a significant therapeutic target, with agonists being explored for neuroprotection and selective kinase inhibitors already approved for treating NTRK-fusion-positive malignancies [3, 4].

Other names

Tropomyosin receptor kinase BTrkBBDNF/NT-3 growth factors receptorGP145-TrkBTrk-BNTRK2

The full-length TrkB receptor is activated upon binding its primary ligands, Brain-Derived Neurotrophic Factor (BDNF) or Neurotrophin-4 (NT-4), which induces receptor dimerization and trans-autophosphorylation of specific tyrosine residues in the intracellular domain [1, 2]. This phosphorylation creates docking sites for adapter proteins, triggering the MAPK/ERK, PI3K/Akt, and PLC-gamma signaling pathways that regulate neuronal survival and plasticity [2]. In oncology, small molecule inhibitors like larotrectinib act as ATP-competitive inhibitors that bind to the kinase domain of NTRK fusion proteins, blocking the constitutive signaling that drives tumor growth [3].