title: Essential role for phospholipase D2 activation downstream of ERK MAP kinase in nerve growth factor-stimulated neurite outgrowth from PC12 cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Takeaki
authors.initials: T
authors.lastname: Yokozeki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Maehama
authors.forename: Kouichi
authors.initials: K
authors.lastname: Itoh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites; D016716:PC12 Cells; D010739:Phospholipase D / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D000199:Actins; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; C105606:phospholipase D2; D010739:Phospholipase D