NGF and EGF rapidly activate p21ras in PC12 cells by distinct, convergent pathways involving tyrosine phosphorylation.
Activation of p21ras, demonstrated directly as an increase in p21ras-associated GTP, was induced rapidly but transiently by both nerve growth factor (NGF) and epidermal growth factor (EGF) in PC12 cells. The factors activate p21ras to equal extents and with virtually identical time courses. Growth factor-induced p21ras activation and tyrosine phosphorylation have similar time courses and sensitivities to genistein inhibition, indicating that p21ras activation is a result of tyrosine kinase activity. Furthermore, PC12 mutants lacking the Trk NGF receptor tyrosine kinase also lack NGF-inducible p21ras activation. The protein kinase inhibitor K252a and the methyltransferase inhibitor MTA abolish NGF-induced, but not EGF-induced, p21ras activation--effects correlated with inhibition only of NGF-induced tyrosine phosphorylation. In spite of differences in sensitivity to genistein, MTA, and K252a, EGF- and NGF-stimulated p21ras activation are not additive, implying that they do share at least one step in common.
Qiu
M S
MS
Department of Biology, University of Iowa, Iowa City 52242.
Green
S H
SH
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D019833:Genistein; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D026121:Indole Alkaloids; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014443:Tyrosine
D002227:Carbazoles; D026121:Indole Alkaloids; D007529:Isoflavones; D009414:Nerve Growth Factors; D006153:Guanosine Diphosphate; D014443:Tyrosine; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; C049985:staurosporine aglycone; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)