title: K-252a and staurosporine selectively block autophosphorylation of neurotrophin receptors and neurotrophin-mediated responses.
abstract: The same receptor tyrosine kinase (RTK) can mediate strikingly different biological responses in a fibroblast as opposed to a neuron. We have compared the rapidly induced tyrosine phosphorylations mediated by various RTKs in both NIH3T3 fibroblasts and in the PC12 neuronal precursor cell line and found that each RTK induces a distinct pattern of protein tyrosine phosphorylations in the two cell types. These findings are consistent with a model in which various cell types present a given RTK with different menus of signal transduction components, allowing the same RTK to elicit fundamentally distinct biological responses. Although there are obvious overlaps in the tyrosine phosphorylations induced by different RTKs in the same cell, there are also clear differences. The attempt to dissect these differences revealed that the kinase inhibitors K-252a and staurosporine inhibit RTK autophosphorylation and thus the biological consequences of receptor/ligand interaction. These inhibitors displayed substantially greater specificity for a subset of RTKs (including the neurotrophin receptors) than for other RTKs and acted as remarkably selective blockers of neurotrophin action in both neuronal and nonneuronal cells. A potential therapeutic application for these inhibitors is discussed.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591.
authors.forename: S H
authors.initials: SH
authors.lastname: Nye
authors.forename: S P
authors.initials: SP
authors.lastname: Squinto
authors.forename: D J
authors.initials: DJ
authors.lastname: Glass
authors.forename: T N
authors.initials: TN
authors.lastname: Stitt
authors.forename: P
authors.initials: P
authors.lastname: Hantzopoulos
authors.forename: M J
authors.initials: MJ
authors.lastname: Macchi
authors.forename: N S
authors.initials: NS
authors.lastname: Lindsay
authors.forename: N Y
authors.initials: NY
authors.lastname: Ip
authors.forename: G D
authors.initials: GD
authors.lastname: Yancopoulos
mesh_terms: D016475:3T3 Cells; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D006133:Growth Substances / Q000502:physiology*; D026121:Indole Alkaloids; D051379:Mice; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D017475:Receptors, Nerve Growth Factor; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine
chemical_list: D000470:Alkaloids; D002227:Carbazoles; D006133:Growth Substances; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D019311:Staurosporine