PC12 cell neuronal differentiation is associated with prolonged p21 ras activity and consequent prolonged ERK activity

Abstract

Expression of oncogenic ras in PC12 cells causes neuronal differentiation and sustained protein tyrosine phosphorylation and activity of extracellular signal-regulated kinases (ERKs), p42 erk2 and p44 erk1 . 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 p21 ras but serve as the primary downstream effectors of p21 ras . Treatment of PC12 cells with nerve growth factor or fibroblast growth factor results in neuronal differentiation and in a sustained elevation of p21 ras 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 p21 ras ERKs. These data indicate that transient activation of p21 ras and, consequently, ERKs is not sufficient for induction of neuronal differentiation. Prolonged ERK activity is required: a consequence of sustained activation of p21 ras by the growth factor receptor protein tyrosine kinase.