AN ALTERNATIVELY SPLICED FORM OF THE NERVE GROWTH-FACTOR RECEPTOR TRKA CONFERS AN ENHANCED RESPONSE TO NEUROTROPHIN-3

TrkA, a member of the receptor tyrosine kinase family, binds nerve gro wth factor (NGF) and subsequently activates intracellular signaling pa thways. Previous studies have found variable and weak interaction of t he TrkA receptor with neurotrophin 3 (NT-3), another member of the NGF family. TrkA is expressed in two splice forms, differing in the prese nce of an 18-bp exon in the extracellular domain. The biological respo nses of each isoform of the TrkA receptor were tested after transfecti on into the cell line PC12(nnr5), a variant of PC12 cells lacking func tional TrkA protein. NGF was found to activate each form of the recept or comparably. However, the TrkA isoform containing the variable exon showed significantly higher activation by NT-3, which was detected by stimulation of TrkA autophosphorylation, induction of ZIF268 transcrip tion, and cellular differentiation. Function-perturbing antibodies to the p75 low-affinity NGF receptor potentiated the NT-3 responses of bo th forms of TrkA in the transfected PC12(nnr5) cell lines, suggesting that the low-affinity NGF receptor suppresses the ability of TrkA to r espond to NT-3.