Naito_2017_Neurosci.Res_116_10

Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPsigma). TrkC-PTPsigma specifically induces excitatory synapses in a kinase domain-independent manner. TrkC has distinct extracellular domains for PTPsigma- and NT-3-binding and thus may bind both ligands simultaneously. Indeed, NT-3 enhances the TrkC-PTPsigma interaction, thus facilitating synapse induction at the pre-synaptic side and increasing pre-synaptic vesicle recycling in a kinase-independent fashion. A crystal structure study has revealed the detailed structure of the TrkC-PTPsigma complex as well as competitive modulation of TrkC-mediated synaptogenesis by heparan sulfate proteoglycans (HSPGs), which bind the same domain of TrkC as PTPsigma. Thus, there is strong evidence supporting a role for the TrkC-PTPsigma complex in mechanisms underlying the fine turning of neural connectivity. Furthermore, disruption of the TrkC-PTPsigma complex may be the underlying cause of certain psychiatric disorders caused by mutations in the gene encoding TrkC (NTRK3), supporting its role in cognitive functions.