Abstract
Induction of neuronal differentiation of the rat pheochromocytoma cell line, PC12 cells, by nerve growth factor (NGF) requires activation of the mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK). cAMP-dependent protein kinase (protein kinase A (PKA)) also can induce differentiation of these cells. Like NGF, the ability of PKA to differentiate PC12 cells is associated with a sustained activation of ERKs. Here we show that maximal sustained activation of ERK1 by NGF requires PKA. Inhibitors of PKA partially blocked activation of ERK1 by NGF but had no effect on activation of ERK1 by EGF. Inhibition of PKA also reduced the ability of NGF and cAMP, but not EGF, to activate the transcription factor Elk-1, reduced the induction of both immediate early and late genes after NGF treatment, and blocked the nuclear translocation of ERK1 induced by NGF. We propose that PKA is an important contributor to the activation of ERK1 by NGF and is required for maximal induction of gene expression by NGF.
Highlights
Induction of neuronal differentiation of the rat pheochromocytoma cell line, PC12 cells, by nerve growth factor (NGF) requires activation of the mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK). cAMP-dependent protein kinase (protein kinase A (PKA)) can induce differentiation of these cells
Epidermal growth factor (EGF) activation of ERKs was not blocked by H89 at 5 or 20 min in the data presented in Fig. 1D, suggesting that H89 was preferentially acting on kinases downstream of NGF at this concentration
NGF Activation of ERK1 Is Reduced by the Protein Kinase Inhibitor PKI—PKA can be inhibited by the protein kinase inhibitor (PKI), a physiological inhibitor of PKA [18, 19]
Summary
Vol 273, No 14, Issue of April 3, pp. 8240 –8247, 1998 Printed in U.S.A. The Cyclic Adenosine Monophosphate-dependent Protein Kinase (PKA) Is Required for the Sustained Activation of Mitogen-activated Kinases and Gene Expression by Nerve Growth Factor*. Induction of neuronal differentiation of the rat pheochromocytoma cell line, PC12 cells, by nerve growth factor (NGF) requires activation of the mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK). We have recently identified a novel Ras-independent pathway by which cAMP induces sustained activation of ERKs in PC12 cells [12] This pathway involves the Ras-related small G protein Rap as well as the cAMP-dependent protein kinase, PKA. We examine the possibility that PKA participates in NGF signaling to the MAP kinase cascade by providing NGF a Ras-independent pathway to ERKs. We show that inhibition of PKA can inhibit signaling of NGF to ERK, to the transcription factor Elk-1, and to a specific marker gene of differentiation and can block the nuclear translocation of ERK1 induced by NGF. We propose that PKA participates in NGF signaling to ERKs, in part via the activation of Rap, and that this pathway contributes to the sustained activation of ERKs that characterizes NGF signaling
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