TrkC has distinct spatiotemporal dynamics compared to TrkA and TrkB

Abstract

Neurotrophins (NGF, BDNF, NT-3, NT-4) are critical regulators of neuronal development and have been implicated in a range of neurodegenerative disorders. They signal through three tropomyosin receptor kinase receptors (TrkA, TrkB and TrkC). TrkC can exist as an alternately spliced isoform (TrkCKID) that includes an exon-16 derived kinase insert domain (KID). Here, we have utilised FRET and BRET biosensors to compare the spatiotemporal dynamics of TrkA, TrkB and TrkC. TrkA and TrkB displayed robust concentration-dependent ERK signalling, dimerisation and trafficking, and also provided evidence for receptor activation by non-canonical ligands. While the KID-lacking TrkCdeltaKID showed ERK signalling comparable to TrkA and TrkB, TrkCKID displayed markedly reduced downstream ERK signalling. Interestingly, TrkCdeltaKID and TrkCKID exhibited slower trafficking away from the cell surface than TrkA or TrkB, but a strong ability to dimerise. Overall, these findings reveal that TrkC possesses unique regulatory mechanisms that may provide opportunities for tailored neurotrophic drug discovery.