The tyrosine kinase inhibitor tyrphostin blocks the cellular actions of nerve growth factor.
A series of the synthetic protein kinase inhibitors known as tyrphostins were examined for their effects on the tyrosine autophosphorylation of the pp140c-trk, nerve growth factor (NGF) receptor. One of the tyrphostins, AG879, inhibited NGF-dependent pp140c-trk tyrosine phosphorylation, but did not affect tyrosine phosphorylation of epidermal growth 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-dependent, although inhibition of pp38 phosphorylation occurred earlier and at lower concentrations of the compound. AG879 also inhibited NGF-induced PLC-gamma 1 phosphorylation, phosphatidylinositol-3 (PI3) kinase activation, the association of the tyrosine-phosphorylated proteins pp100 and pp110 with the p85 subunit of PI-3 kinase, mitogen activated protein and raf-1 kinases, and c-fos induction. In addition, AG879 inhibited NGF-induced neurite outgrowth in PC12 cells. These data indicate that tyrosine kinase activity of the pp140c-trk NGF receptor is essential for the cellular actions of this growth factor.
Ohmichi
M
M
Department of Physiology, University of Michigan School of Medicine, Ann Arbor 48109.
Pang
L
L
Ribon
V
V
Gazit
A
A
Levitzki
A
A
Saltiel
A R
AR
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002396:Catechols / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D019000:Phosphotyrosine; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D020032:Tyrphostins
C081020:AG-879; D001597:Benzylidene Compounds; D002396:Catechols; D009414:Nerve Growth Factors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D020032:Tyrphostins; C060152:tyrphostin 47; D019000:Phosphotyrosine; D014443:Tyrosine; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases