Go 6976 is a potent inhibitor of neurotrophin-receptor intrinsic tyrosine kinase

We report here that addition of the protein kinase C inhibitor Gd 6976 bloc ked neurotrophin-induced signaling and autophosphorylation of neurotrophin- specific tyrosine kinase (Trk) receptors, either Trk B in cortical neurons or Trk A in GT1-1-trk9 cells, The effect of Go 6976 on Trk autophosphorylat ion was not inhibited by 100 mu M orthovanadate, suggesting that the block was not due to the activation of tyrosine phosphatases, Moreover, addition of 10-100 nM concentrations of Go 6976 inhibited either Trk B or Trk A intr insic kinase activity in cell-free assays, Gb 6976 also blocked the ability of brain-derived neurotrophic factor to promote cortical neuronal survival and the ability of nerve growth factor to promote PC12 cell survival and d ifferentiation. These results suggest that Go 6976, besides its known inhib itory effects on lipid- and calcium-dependent isoforms of protein kinase C, can also inhibit neurotrophin signaling by directly inhibiting the intrins ic Trk.