THE TYROSINE KINASE INHIBITOR TYRPHOSTIN BLOCKS THE CELLULAR ACTIONS OF NERVE GROWTH-FACTOR

A series of the synthetic protein kinase inhibitors known as tyrphosti ns were examined for their effects on the tyrosine autophosphorylation of the pp140c-trk, nerve growth factor (NGF) receptor. One of the tyr phostins, AG879, inhibited NGF-dependent pp140c-trk tyrosine phosphory lation, but did not affect tyrosine phosphorylation of epidermal growt h factor or platelet-derived growth factor receptors. In addition, the tyrosine phosphorylation of the receptor-associated protein pp38 was also attenuated by the tyrphostin. This effect was time- and dose-depe ndent, although inhibition of pp38 phosphorylation occurred earlier an d at lower concentrations of the compound. AG879 also inhibited NGF-in duced PLC-gamma1 phosphorylation, phosphatidylinositol-3 (PI3) kinase activation, the association of the tyrosine-phosphorylated proteins pp 100 and pp110 with the p85 subunit of PI-3 kinase, mitogen activated p rotein and raf-1 kinases, and c-fos induction. In addition, AG879 inhi bited NGF-induced neurite outgrowth in PC12 cells. These data indicate that tyrosine kinase activity of the pp140c-trk NGF receptor is essen tial for the cellular actions of this growth factor.