title: Phosphatidic acid inhibits ceramide 1-phosphate-stimulated macrophage migration.
abstract: Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ouro
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Lide
authors.initials: L
authors.lastname: Arana
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Io-Guané
authors.initials: IG
authors.lastname: Rivera
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ordoñez
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gomez-Larrauri
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Presa
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Simón
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Trueba
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gangoiti
authors.affiliation: Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain. Electronic address: antonio.gomez@ehu.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez-Muñoz
mesh_terms: D000818:Animals; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D010712:Phosphatidic Acids / Q000494:pharmacology*
chemical_list: D002518:Ceramides; D010712:Phosphatidic Acids; C065576:ceramide 1-phosphate
keywords: 4-Bromo-5-hydroxy-2-nitrobenzhydryl (BHNB)-ceramide 1-phosphate (BHNB-C1P); Cell migration; Ceramide 1-phosphate; Lysophosphatidic acid (LPA); Macrophages; N-Hexadecanoyl-d-erythro-sphingosine-1-phosphate (C16:0-ceramide 1-phosphate); Phosphatidic acid; Phosphatidic acid (PA); Sphingolipids; sn-1,2-Diacylglycerol (DAG)