Nerve growth factor–Tropomyosin receptor kinase A signaling pathway (NGF–TrkA)

The Nerve growth factor–Tropomyosin receptor kinase A (NGF–TrkA) signaling pathway is a fundamental biological axis responsible for the growth, differentiation, and survival of peripheral sensory and sympathetic neurons (UniProt, 2024). The pathway is activated when the neurotrophin NGF binds to the TrkA receptor tyrosine kinase, leading to receptor dimerization and the activation of downstream signaling cascades including the PI3K/Akt, Ras/MAPK, and PLC-gamma pathways (Huang & Reichardt, 2003). In adult physiology, this signaling axis plays a pivotal role in pain modulation, where NGF acts as a potent mediator of hyperalgesia by sensitizing nociceptors in response to injury or inflammation (Mantyh et al., 2011). Pathologically, chromosomal rearrangements involving the NTRK1 gene result in constitutive kinase activation, driving various cancers such as secretory breast carcinoma and lung adenocarcinoma (Vaishnavi et al., 2015). Therapeutic interventions targeting this pathway include monoclonal antibodies like tanezumab, which neutralizes NGF to alleviate chronic pain, and small-molecule inhibitors like larotrectinib, which target the Trk kinase domain for the treatment of NTRK fusion-positive malignancies (Drilon et al., 2018).

Other names

NGF/TrkA axisNerve growth factor receptor signalingNTRK1 signaling pathwayNGF-TrkA pathway

Inhibition of the NGF–TrkA signaling pathway is achieved either by neutralizing the ligand (NGF) using monoclonal antibodies to prevent receptor binding or by small-molecule inhibition of the TrkA receptor's tyrosine kinase activity to block downstream signaling cascades.