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The Trk family of receptor tyrosine kinases for the neurotrophins. TrkA is primarily a receptor for NGF, TrkB a receptor for BDNF and NT-4/5, and TrkC a receptor for NT-3. Because of the high degree of structural homology among both the neurotrophins and the Trk receptors, there is some degree of cross-activation between factors and receptors. For example, NT-3 can bind to and activate TrkB under some conditions, as indicated by the dashed arrow. These distinct receptors allow various neurons to respond selectively to the different neurotrophins.

Signal-transduction mechanisms in nerve growth factor (NGF)-mediated neuronal survival and differentiation. NGF binds to TrkA and induces autophosphorylation on three different sites in the intracellular domain. One site interacts with SHC, which eventually leads to the activation of mitogen-activated protein kinase (MAPK) and transcription. TrkA also induces tyrosine phosphorylation of suc-associated neurotrophic factor-induced target (SNT) via a mechanism independent of all known signaling mechanisms. MAPK-induced transcription and SNT tyrosine phosphorylation are believed to be important in neuronal differentiation. TrkA autophosphorylation also activates phosphatidylinositol-3-kinase (PI3K) by recruiting it to the membrane. PI3K generates PI-3,4,5-trisphosphate from PI-4,5-bisphosphate. PI-3,4,5-trisphosphate is hydrolyzed to yield PI-3,4-bisphosphate, which activates Akt by translocating it to the membrane. Activated Akt can promote neuronal survival. PLC, phospholipase C; SOS, son of sevenless; MEK, MAPK/Erk kinase; Grb2, growth factor receptor binding protein; SHC, SH2-containing protein.

Mechanism of action of NGF. NGF binds to a high-affinity tyrosine kinase receptor, TrkA, on the plasma membrane to induce phosphorylation of TrkA at two different tyrosine residues. These phosphorylated tyrosines serve to tether various adapter proteins or phospholipase C (PLC), which, in turn, activate three major signaling pathways: the PI 3 kinase pathway leading to activation of Akt kinase, the ras pathway leading to MAP kinases, and the PLC pathway leading to release of intracellular Ca²⁺ and activation of PKC. The ras and PLC pathways primarily stimulate processes responsible for neuronal differentiation, while the PI 3 kinase pathway is primarily involved in cell survival.

The Trk family of neurotrophins transmembrane receptors.
All neurotrophins bind to one or more receptor of the Trk protein family. (tropomyosine receptor kinase, TrkA, B, C) Trk receptors are a small subfamily consisting of three members out of the large superfamily of several hundred proteins with tyrosine kinase enzymatic activity that also includes receptors for EGF, insulin, FGF, PDGF and numerous other growth factors. The Trk receptor tyrosine kinases are characterized by a specific combination of structural motives: In their extracellular domains: three tandem repeat leucine-rich motives are flanked by two cystein clusters. The main contacts between the Trk receptors and their ligands occur within two Ig-like C2 type domains. The protein sequences of the intracellular, enzymatically active, tyrosine kinase domains are highly conserved in the three receptors. The neurotrophins bind to the Trk receptors with strong (thick arrows) and weak interactions (thin arrows). Both strong and weak (also sometimes called preferred and non-preferred) interactions are relevant in vivo.
Simplified sketch of Trk receptor signaling. Upon dimerization several tyrosine residues become phosphorylated (PY) in the intracellular domains of the Trk receptors. This enables association of signaling molecules, in particular various adaptor proteins to the receptors that in turn trigger different cellular responses, including differentiation and neurite outgrowth, promotion of survival through blockade of apoptotic pathways and regulation of activity-dependent plasticity. Duration and extent of signaling pathway activation depends on the type of cell and on the Trk receptor activated. The pathways cross talk to each other (not shown).