NTRK1 (neurotrophic receptor tyrosine kinase 1; HGNC:8031, NCBI Gene ID 4914) is a human locus mapped to chromosome band 1q23.1 that encodes high-affinity nerve growth factor receptor tyrosine kinase TrkA (796 aa). NTRK1 acts in NGF-TrkA-MAPK/PI3K nociceptor survival & oncogenic NTRK gene fusions, together with NGF (Nerve Growth Factor Gene), BDNF (Brain-Derived Neurotrophic Factor), and Receptor Tyrosine Kinases. Encodes the TrkA receptor tyrosine kinase for nerve growth factor; mutated in CIPA and rearranged in solid tumors.
Congenital insensitivity to pain with anhidrosis (CIPA / HSAN4); target of larotrectinib & entrectinib
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 17-exon gene on chromosome 1q23.1 encoding a 796-amino-acid single-pass transmembrane receptor comprising extracellular leucine-rich repeats and two immunoglobulin-like domains that bind NGF, a transmembrane helix, and an intracellular tyrosine kinase domain.
Cellular & Tissue Expression Profile: Expressed in developing and adult peptidergic dorsal root and trigeminal ganglion nociceptors, postganglionic sympathetic neurons innervating eccrine sweat glands, and basal forebrain cholinergic neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Upon binding homodimeric beta-NGF, TrkA dimerizes and trans-autophosphorylates conserved cytoplasmic tyrosines (Tyr490, Tyr670/674/675, Tyr785), recruiting Shc, PLC-gamma, PI3K-AKT1, and RAS-MAPK cascades that sustain axonal outgrowth and acutely phosphorylate TRPV1 to lower thermal pain thresholds.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations in NTRK1 cause congenital insensitivity to pain with anhidrosis (CIPA, HSAN type IV), characterized by complete absence of nociceptive and sympathetic sweat gland innervation, recurrent hyperpyrexia, and self-mutilating injuries, whereas somatic chromosomal rearrangements (such as TPM3-NTRK1) drive constitutively active TrkA signaling across diverse pediatric and adult malignancies.
Therapeutic & Clinical Pharmacology: Tumor-agnostic TRK tyrosine kinase inhibitors larotrectinib, entrectinib, and repotrectinib are FDA-approved for NTRK1/2/3 fusion-positive solid tumors, while peripherally restricted TrkA inhibitors target osteoarthritic pain.