Gö 6976 is a potent inhibitor of neurotrophin-receptor intrinsic tyrosine kinase.
We report here that addition of the protein kinase C inhibitor Gö 6976 blocked 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 Gö 6976 on Trk autophosphorylation was not inhibited by 100 microM orthovanadate, suggesting that the block was not due to the activation of tyrosine phosphatases. Moreover, addition of 10-100 nM concentrations of Gö 6976 inhibited either Trk B or Trk A intrinsic kinase activity in cell-free assays. Gö 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 differentiation. These results suggest that Gö 6976, besides its known inhibitory effects on lipid- and calcium-dependent isoforms of protein kinase C, can also inhibit neurotrophin signaling by directly inhibiting the intrinsic Trk.
Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
M M
MM
Behrens
U
U
Strasser
D W
DW
Choi
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D016716:PC12 Cells; D010766:Phosphorylation; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D007211:Indoles; D007527:Isoenzymes; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; C081021:Go 6976; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases