Neurotrophic receptor tyrosine kinase 1 (TrkA) and Nerve growth factor receptor (p75NTR) (TrkA/p75NTR)

The nerve growth factor (NGF) receptor system is composed of two distinct transmembrane proteins: the high-affinity neurotrophic receptor tyrosine kinase 1 (TrkA) and the low-affinity nerve growth factor receptor (p75NTR) (UniProt P04629, P08138). TrkA is a receptor tyrosine kinase that, upon binding NGF, initiates intracellular signaling cascades such as the PI3K/Akt and MAPK pathways, which are essential for the survival, growth, and differentiation of sensory and sympathetic neurons (PubMed PMID: 11485740). The p75NTR receptor, a member of the tumor necrosis factor receptor superfamily, acts as a versatile modulator; it can increase the affinity of TrkA for NGF or, in the absence of TrkA, bind pro-neurotrophins to trigger apoptotic pathways (PubMed PMID: 12403979). This dual-receptor system is a major therapeutic target in oncology and pain management. In cancer, chromosomal rearrangements leading to NTRK1 fusions result in constitutive TrkA activation, which is effectively treated by selective inhibitors like larotrectinib and entrectinib (NIH/NCI). In the context of chronic pain, the NGF/TrkA axis is targeted by monoclonal antibodies like tanezumab that sequester NGF, although these have been associated with safety concerns such as rapidly progressive osteoarthritis (PubMed PMID: 31053405).

Other names

NTRK1NGFRCD271p75TRKMTCTNFRSF16High-affinity nerve growth factor receptorLow-affinity nerve growth factor receptorTropomyosin receptor kinase A

Inhibition of the TrkA tyrosine kinase domain, sequestration of the NGF ligand to prevent receptor binding, and allosteric modulation of p75NTR signaling.