TrkAs

TrkAs refers to the TrkA receptor proteins, a subset of the Trk receptor family of receptor tyrosine kinases. They bind nerve growth factor (NGF) with high affinity and initiate intracellular signaling that promotes neuronal survival, differentiation, and maintenance, especially in sympathetic and certain sensory neurons. TrkA is encoded by the NTRK1 gene in humans.

Structure and mechanism: TrkA is a single-pass transmembrane protein with an extracellular ligand-binding domain containing immunoglobulin-like motifs, a transmembrane region, and an intracellular tyrosine kinase domain. Upon NGF binding, TrkA dimerizes and autophosphorylates on multiple tyrosine residues, creating docking sites for adaptor proteins such as Shc, FRS2, and PLCγ, and activating downstream pathways including MAPK/ERK, PI3K/Akt, and PLCγ. These pathways regulate gene expression, cytoskeletal dynamics, and cell survival.

Expression and isoforms: TrkA is expressed in several populations of sensory and sympathetic neurons during development and in adulthood. There are also truncated isoforms, such as TrkA.T1, that lack kinase activity and can modulate signaling through interactions with other proteins and cellular processes.

Clinical relevance: Inherited loss-of-function mutations in NTRK1 cause congenital insensitivity to pain with anhidrosis (CIPA). Somatic NTRK1 fusions can drive oncogenesis in rare cancers, and TRK inhibitors (larotrectinib, entrectinib) are approved for tumors harboring NTRK fusions.