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 tyrosine protein kinase receptors. These receptors, designated TrkC K2 and TrkC K3, have the same amino acid sequences as gp145trkC (now designated 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 site of the Trk receptor family. Upon interaction with their cognate ligand, NT-3, all three TrkC receptor isoforms become rapidly phosphorylated on tyrosine residues and induce DNA synthesis in quiescent cells. However, only TrkC K1 has mitogenic activity in NIH3T3 cells and induces neuronal differentiation of PC12 cells. The different biological properties of these TrkC receptor isoforms probably result from their engagement with different signaling pathways. Whereas TrkC K1 phosphorylates phospholipase C gamma 1 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 observations suggest that the trophic activities of NT-3 in the mammalian nervous system might be mediated by different TrkC receptor isoforms.