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J. Biol. Chem., Vol. 279, Issue 36, 37870-37877, September 3, 2004

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Essential Role for Phospholipase D2 Activation Downstream of ERK MAP Kinase in Nerve Growth Factor-stimulated Neurite Outgrowth from PC12 Cells^*

Hiroshi Watanabe, Takeaki Yokozeki, Masakazu Yamazaki, Hideyuki Miyazaki¶, Takehiko Sasaki||**, Tomohiko Maehama, Kouichi Itoh, Michael A. Frohman, and Yasunori Kanaho¶¶

From the Department of Pharmacology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan, Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Hirosawa, Wako, Saitama 351-0198, Japan, the ^¶Department of Biological Information, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan, the ^||The 21st Century Center of Excellence Program, Akita University School of Medicine, 1-1-1 Honda, Akita 010-8543, Japan, the ^**Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan, the Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki-city, Kagawa 769-2193, Japan, and the Center for Developmental Genetics & Department of Pharmacology, State University of New York, Stony Brook, New York 11794-5140

The signaling pathway that triggers morphological differentiation of PC12 cells is mediated by extracellular signal-regulated kinase (ERK), the classic mitogen-activated protein (MAP) kinase. However, mediators of the pathway downstream of ERK have not been identified. We show here that phospholipase D2 (PLD2), which generates the pleiotropic signaling lipid phosphatidic acid (PA), links ERK activation to neurite outgrowth in nerve growth factor (NGF)-stimulated PC12 cells. Increased expression of wild type PLD2 (WT-PLD2) dramatically elongated neurites induced by NGF stimulation or transient expression of the active form of MAP kinase-ERK kinase (MEK-CA). The response was activity-dependent, because it was inhibited by pharmacological suppression of the PLD-mediated PA production and by expression of a lipase-deficient PLD2 mutant. Furthermore, PLD2 was activated by MEK-CA, whereas NGF-stimulated PLD2 activation and hypertrophic neurite extension were blocked by an MEK-specific inhibitor. Taken together, these results provide evidence that PLD2 functions as a downstream signaling effector of ERK in the NGF signaling pathway, which leads to neurite outgrowth by PC12 cells.

Received for publication, March 8, 2004 , and in revised form, June 24, 2004.

^* This work was supported by the research grants from the Ministry of Education, Science, Sports and Culture, Japan, the Yamanouchi Foundation for Research on Metabolic Disorders, and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Science, Sports and Culture, Japan (to Y. K.) and by Grant DK64166 from the National Institutes of Health (to M. A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed. Tel.: 81-3-3823-5280; Fax: 81-3-3823-5284; E-mail: ykanaho{at}rinshoken.or.jp.

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