TRKA

Official Full Name

neurotrophic receptor tyrosine kinase 1

Organism

Homo sapiens

GeneID

4914

Background

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

Synonyms

MTC; TRK; TRK1; TRKA; Trk-A; p140-TrkA;

Bio Chemical Class

Kinase

Protein Sequence

MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLHHLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRLNLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQGPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMKSGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWCIPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYTLLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSVAVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKMLVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQALAQAPPVYLDVLG

Open

Disease

Adrenal cancer, Alzheimer disease, Breast cancer, Chronic pain, Colorectal cancer, General pain disorder, Lymphoma, Non-small-cell lung cancer, Pain, Pancreatic cancer, Pruritus, Psoriasis, Solid tumour/cancer, Thymoma

Approved Drug

3 +

Clinical Trial Drug

10 +

Discontinued Drug

1 +

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Detailed Information

TRKA, encoded by the NTRK1 gene, is a key member of the neurotrophic tyrosine kinase receptor (NTKR) family and represents a typical type I transmembrane receptor tyrosine kinase. The NTRK1 gene is located on human chromosome 1q23.1 and contains 17 exons. Alternative splicing generates multiple transcript variants, with the full-length TrkA isoform, consisting of 796 amino acids, representing the primary functional form. The TRKA receptor is composed of an extracellular ligand-binding domain, a single transmembrane segment, and an intracellular tyrosine kinase domain. Its extracellular region contains leucine-rich repeats and immunoglobulin-like domains responsible for the selective recognition and binding of neurotrophic factors. Upon binding to nerve growth factor (NGF), TRKA undergoes homodimerization, which triggers autophosphorylation of the intracellular domain and activates downstream signaling pathways. TRKA activation is largely ligand-specific, predominantly responding to NGF, although under certain conditions it can bind neurotrophin-3 (NTF3) with lower activation efficiency.

Figure 1. TrkA receptor structure and signaling pathways. (Conroy JN, et al., 2022.)

Expression and Functional Roles

TRKA is highly expressed in peripheral sensory and sympathetic neurons, where it plays a crucial role in nociceptors. In the central nervous system, TRKA is present in basal forebrain cholinergic neurons, the striatum, and specific cortical regions, contributing to neuronal survival, differentiation, and synaptic plasticity. From an evolutionary perspective, TRKA is highly conserved across vertebrates, underscoring its essential role in nervous system development. As a central signaling regulator, TRKA recruits downstream signaling complexes through multiple adaptor proteins, including SHC1, FRS2, SH2B1, SH2B2, and PLCG1, forming a complex signaling network. This multilayered regulation allows TRKA to precisely control neuronal development and maintain neural system homeostasis.

Biological Functions and Pathological Implications

During nervous system development, NGF-mediated TRKA signaling is indispensable for neuronal survival, differentiation, and maturation. In embryonic stages, TRKA activates the Ras-MAPK pathway to promote precursor cell differentiation while engaging PI3K-AKT signaling to inhibit apoptosis, ensuring the proper establishment of neuronal populations. In the peripheral nervous system, NGF-dependent sympathetic and sensory neurons, particularly nociceptors, rely on TRKA signaling to maintain viability and functional characteristics. Functional loss of TRKA in experimental models leads to widespread sensory neuron apoptosis and severe peripheral nervous defects. Beyond development, TRKA continues to regulate synaptic plasticity, neurotransmitter release, and post-injury neural regeneration in mature neurons.

TRKA dysfunction is associated with several human diseases. Congenital insensitivity to pain with anhidrosis (CIPA) arises from TRKA mutations, manifesting as loss of pain perception, impaired temperature regulation, and cognitive deficits. In this context, inactivating mutations in NTRK1 impair TRKA function, disrupting nociceptor development and signaling. TRKA is also aberrantly activated in various cancers. In thyroid medullary carcinoma, NTRK1 gene fusions (e.g., ETV6-NTRK1) generate constitutively active chimeric proteins that sustain survival and proliferation signaling, with similar fusion events observed in colorectal cancer and gliomas. Notably, the TrkA-III splice variant is upregulated in certain malignancies, including neuroblastoma and breast cancer. This isoform lacks key extracellular domains, enabling ligand-independent activation. TrkA-III promotes tumor proliferation and angiogenesis through persistent activation of AKT1 and NF-κB pathways while antagonizing neuronal differentiation signals.

In bone metabolism, TRKA has been implicated in fracture healing. Experimental models indicate that TRKA expression is reduced in fracture callus tissue with concomitant vascular injury compared to simple fractures, correlating with impaired bone repair. This finding suggests that ischemia may delay fracture healing by inhibiting TRKA signaling, providing a potential molecular target for complex fracture therapies.

Therapeutic Potential and Translational Research

TRKA-targeted inhibitors have emerged as a key strategy in oncology. Early-generation TRK inhibitors, such as larotrectinib and entrectinib, demonstrate notable efficacy against tumors harboring NTRK fusions by competitively binding the TRKA kinase domain and blocking downstream signaling. Resistance may develop due to kinase domain mutations, which has driven the development of next-generation inhibitors capable of overcoming common resistance variants.

In the context of nervous system disorders, TRKA modulators remain under investigation. Given its central role in pain signaling, selective antagonists may offer novel analgesic approaches, though complete inhibition poses risks of neurotoxicity. Strategies under consideration include allosteric modulators that dampen pathological overactivation while preserving basal signaling. In bone repair, localized NGF administration enhances fracture healing in animal studies, whereas systemic delivery may induce adverse effects such as pain, suggesting tissue-specific TRKA targeting or agonist development as future research directions.

Despite progress, challenges remain in fully understanding TRKA biology, including isoform-specific functions, interactions with other neurotrophic receptors, and dynamic signaling in the tumor microenvironment. Advances in protein engineering and structural biology may enable the design of domain-specific bifunctional antibodies or PROTACs for targeted TRKA modulation. Standardized detection of NTRK fusions, including RNA sequencing and pan-TRK immunohistochemistry, is essential for identifying patients likely to benefit from targeted therapies. Integrating fundamental research with clinical translation will be key to realizing the full therapeutic potential of TRKA.

Reference

Hirose M, Kuroda Y, Murata E. NGF/TrkA Signaling as a Therapeutic Target for Pain. Pain Pract. 2016 Feb;16(2):175-82.
Trouvilliez S, Lagadec C, Toillon RA. TrkA Co-Receptors: The Janus Face of TrkA? Cancers (Basel). 2023 Mar 23;15(7):1943.
Conroy JN, Coulson EJ. High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair. J Biol Chem. 2022 Mar;298(3):101568.

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