TRKC ENCODES MULTIPLE NEUROTROPHIN-3 RECEPTORS WITH DISTINCT BIOLOGICAL PROPERTIES AND SUBSTRATE SPECIFICITIES

The trkC gene product gp145trkC is a high affinity signaling receptor for neurotrophin-3 (NT-3), a member of the NGF family of neurotrophic factors. We now report that trkC encodes at least two additional tyros ine protein kinase receptors. These receptors, designated TrkC K2 and TrkC K3, have the same amino acid sequences as gp145trkC (now designat ed TrkC K1) except for the presence of 14 and 25 additional amino acid residues between kinase subdomains VII and VIII, just downstream from the TDYYR motif which encompasses the putative autophosphorylation si te of the Trk receptor family. Upon interaction with their cognate lig and, NT-3, all three TrkC receptor isoforms become rapidly phosphoryla ted on tyrosine residues and induce DNA synthesis in quiescent cells. However, only TrkC K1 has mitogenic activity in NIH3T3 cells and induc es neuronal differentiation of PC12 cells. The different biological pr operties of these TrkC receptor isoforms probably result from their en gagement with different signaling pathways. Whereas TrkC K1 phosphoryl ates phospholipase Cgamma1 and phosphatidylinositol-3 kinase, TrkC K2 and TrkC K3 do not. TrkC K2 and transcripts encoding TrkC K3 have been identified in various structures of the adult murine brain. These obs ervations suggest that the trophic activities of NT-3 in the mammalian nervous system might be mediated by different TrkC receptor isoforms.