TRKB

Official Full Name

neurotrophic receptor tyrosine kinase 2

Organism

Homo sapiens

GeneID

4915

Background

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation. Mutations in this gene have been associated with obesity and mood disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Synonyms

OBHD; TRKB; DEE58; trk-B; EIEE58; GP145-TrkB;

Bio Chemical Class

Kinase

Protein Sequence

MSSWIRWHGPAMARLWGFCWLVVGFWRAAFACPTSCKCSASRIWCSDPSPGIVAFPRLEPNSVDPENITEIFIANQKRLEIINEDDVEAYVGLRNLTIVDSGLKFVAHKAFLKNSNLQHINFTRNKLTSLSRKHFRHLDLSELILVGNPFTCSCDIMWIKTLQEAKSSPDTQDLYCLNESSKNIPLANLQIPNCGLPSANLAAPNLTVEEGKSITLSCSVAGDPVPNMYWDVGNLVSKHMNETSHTQGSLRITNISSDDSGKQISCVAENLVGEDQDSVNLTVHFAPTITFLESPTSDHHWCIPFTVKGNPKPALQWFYNGAILNESKYICTKIHVTNHTEYHGCLQLDNPTHMNNGDYTLIAKNEYGKDEKQISAHFMGWPGIDDGANPNYPDVIYEDYGTAANDIGDTTNRSNEIPSTDVTDKTGREHLSVYAVVVIASVVGFCLLVMLFLLKLARHSKFGMKGPASVISNDDDSASPLHHISNGSNTPSSSEGGPDAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFLAECYNLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFYGVCVEGDPLIMVFEYMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQIAAGMVYLASQHFVHRDLATRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWMPPESIMYRKFTTESDVWSLGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRKNIKGIHTLLQNLAKASPVYLDILG

Open

Disease

Adrenal cancer, Alzheimer disease, Bone growth disorder, Breast cancer, Chronic pain, Colorectal cancer, General pain disorder, Neurodegenerative disorder, Non-small-cell lung cancer, Pruritus, Solid tumour/cancer, Thymoma

Approved Drug

2 +

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

TRKB, encoded by the NTRK2 gene, is a central member of the neurotrophin receptor family and is located on human chromosome 9q22.1. The gene spans over 1.1 Mb and contains 24 exons. Through alternative splicing, NTRK2 produces multiple isoforms, including the full-length receptor (TrkB.FL), which contains a canonical tyrosine kinase domain, and truncated forms such as TrkB.T1 and TrkB.T2, which lack the intracellular kinase domain and may function in signal modulation. Structurally, the TRKB receptor consists of an extracellular ligand-binding domain, a transmembrane helix, and an intracellular kinase domain. The extracellular region includes two cysteine-rich domains and two immunoglobulin-like domains, providing ligand specificity. TRKB primarily binds brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NTF4), and at lower efficiency, neurotrophin-3 (NTF3).

Figure 1. Schematic representation of the genomic structure of the murine TrkB gene.( Tessarollo L, et al., 2022.)

TRKB is widely expressed in the central nervous system, with particularly strong expression in the hippocampus, cerebral cortex, cerebellum, and basal ganglia, consistent with its key role in learning, memory, and synaptic plasticity. During neurodevelopment, its expression is tightly regulated in a spatiotemporal manner, being high in neural progenitors during embryogenesis and later localized mainly in mature neurons and glial cells. Beyond the nervous system, TRKB is also found in cardiovascular tissues, pancreatic β-cells, and bone, indicating broader physiological functions. At the transcriptional level, the NTRK2 promoter contains conserved binding sites for transcription factors such as CREB and NF-κB, which themselves are regulated by neurotrophin signaling, forming a complex feedback network.

Role in Neural Development and Functional Regulation

During neural development, TRKB-mediated signaling plays a critical role in neuronal survival, differentiation, migration, and synapse formation. In embryonic development, BDNF-TRKB signaling activates the Ras-MAPK pathway to promote neuronal differentiation and axon guidance, while the PI3K-AKT pathway suppresses apoptosis to maintain neuronal populations. Postnatally, this signaling is involved in fine-tuning synaptic connectivity, including dendritic spine formation, synapse maturation, and neurotransmitter release. At the molecular level, BDNF binding induces TRKB dimerization and autophosphorylation, recruiting adaptor proteins such as SHC1, FRS2, SH2B1, and PLCγ1 to initiate downstream cascades. Signal endosomes formed through clathrin-mediated endocytosis are crucial for maintaining spatiotemporal specificity, with proteins like retrolinkin and endophilin A1 regulating vesicular transport and ERK pathway activation.

TRKB is especially important for synaptic plasticity. Long-term potentiation (LTP), a cellular mechanism underlying learning and memory, relies heavily on BDNF-TRKB signaling. This pathway regulates NMDA receptor function and synaptic protein synthesis, sustaining enhanced synaptic efficacy. Activation of PLCγ1 leads to IP3 production, triggering intracellular calcium release, which subsequently activates CaMKII and PKC, modulating postsynaptic receptor trafficking and neurotransmitter release. TRKB signaling also engages the mTOR pathway to regulate local protein synthesis, supporting structural and functional synaptic remodeling. Animal studies demonstrate that TRKB deficiency impairs learning, memory, and hippocampal plasticity, highlighting its role in cognitive function.

Implications in Neuropsychiatric Disorders

TRKB dysfunction is associated with multiple neuropsychiatric conditions. Altered TRKB signaling is implicated in mood disorders, where reduced BDNF-TRKB activity contributes to depressive phenotypes, accompanied by hippocampal atrophy and synaptic loss. Chronic stress can suppress BDNF expression through epigenetic modifications, leading to neuronal atrophy, while interventions such as pharmacotherapy or neuromodulation can restore TRKB activity and promote synaptic remodeling. In seizure models, aberrant TRKB expression in the hippocampus may contribute to post-seizure synaptic reorganization, suggesting its potential as a therapeutic target.

Role in Tumor Progression and Targeted Therapy

TRKB also plays complex roles in tumor biology. In neurogenic tumors such as neuroblastoma, TRKB expression often correlates with favorable differentiation, indicating potential tumor-suppressive effects. In contrast, in solid tumors like lung adenocarcinoma, TRKB can act as a pro-metastatic factor. Hypoxic conditions can upregulate TRKB in tumor cells, where it binds BDNF secreted by neurons to activate downstream pathways that promote invasion and metastasis. Mechanistically, TRKB-BDNF interaction triggers Ras-MAPK and PI3K-AKT signaling, enhancing cell migration and angiogenesis. Experimental models show that TRKB deletion significantly reduces metastatic potential, emphasizing its critical role in tumor progression.

In osteosarcoma, TRKB similarly exhibits pro-invasive characteristics. Malignant transformation of human osteoblasts shows elevated TRKB expression, and treatment with tyrosine kinase inhibitors such as K252a induces morphological changes and reduces invasiveness. Mechanistic studies suggest that K252a disrupts actin cytoskeleton dynamics, weakening cell motility. These findings indicate that TRKB may promote tumor invasiveness through regulation of cytoskeletal dynamics.

Given these mechanisms, targeting TRKB has therapeutic potential. First-generation TRK inhibitors have shown efficacy in TRKB-dependent tumors, but systemic inhibition poses risks due to TRKB's essential functions in the central nervous system. Efforts to improve specificity include antibody-drug conjugates and allosteric inhibitors. In depression therapy, TRKB agonist development faces challenges due to receptor desensitization, and alternative strategies involve BDNF-mimetic peptides or small molecules that modulate TRKB dimerization. Advances in structural biology provide opportunities for rational drug design based on the extracellular domain of TRKB, potentially overcoming current limitations.

Reference

Wang Y, Liang J, Xu B, et al. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci. 2024 Jan 1;336:122282.
Zhang JC, Yao W, Hashimoto K. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets. Curr Neuropharmacol. 2016;14(7):721-31.
Enkavi G, Girych M, Moliner R, et al. TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends Biochem Sci. 2024 May;49(5):445-456.
Tessarollo L, Yanpallewar S. TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions. Front Neurosci. 2022 Mar 7;16:847572.

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