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Mol Cell Biol, April 1998, p. 1946-1955, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation

Jun Xing,1,2,3 Jon M. Kornhauser,2,3 Zhengui Xia,2,3,dagger Elizabeth A. Thiele,2,3 and Michael E. Greenberg2,3,*

Program in Biological and Biomedical Sciences1 and Department of Neurobiology,2 Harvard Medical School, and Division of Neuroscience, Department of Neurology, Children's Hospital,3 Boston, Massachusetts 02115

Received 25 August 1997/Returned for modification 24 October 1997/Accepted 23 December 1997

The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.

* Corresponding author. Mailing address: Division of Neuroscience, Department of Neurology, John F. Enders Pediatric Research Laboratories, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 355-8344. Fax: (617) 738-1542. E-mail: greenberg{at}a1.tch.harvard.edu.

dagger Present address: Molecular Toxicology Program, Department of Environmental Health, University of Washington, Seattle, WA 98195.




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