PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity.
Expression of oncogenic ras in PC12 cells causes neuronal differentiation and sustained protein tyrosine phosphorylation and activity of extracellular signal-regulated kinases (ERKs), p42erk2 and p44erk1. Oncogenic N-ras-induced neuronal differentiation is inhibited by compounds that block ERK protein tyrosine phosphorylation or ERK activity, indicating that ERKs are not only activated by p21ras but serve as the primary downstream effectors of p21ras. Treatment of PC12 cells with nerve growth factor or fibroblast growth factor results in neuronal differentiation and in a sustained elevation of p21ras activity, of ERK activity, and of ERK tyrosine phosphorylation. Epidermal growth factor, which does not cause neuronal differentiation, stimulates only transient (< 1 hr) activation of p21ras and ERKs. These data indicate that transient activation of p21ras and, consequently, ERKs is not sufficient for induction of neuronal differentiation. Prolonged ERK activity is required: a consequence of sustained activation of p21ras by the growth factor receptor protein tyrosine kinase.
Qui
M S
MS
Department of Biology, University of Iowa, Iowa City 52242.
Green
S H
SH
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D011905:Genes, ras; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D019000:Phosphotyrosine; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D007527:Isoenzymes; D009414:Nerve Growth Factors; D011506:Proteins; D006153:Guanosine Diphosphate; D019000:Phosphotyrosine; D014443:Tyrosine; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D016283:Proto-Oncogene Proteins p21(ras)