title: Convergent regulation of neuronal differentiation and Erk and Akt kinases in human neural progenitor cells by lysophosphatidic acid, sphingosine 1-phosphate, and LIF: specific roles for the LPA1 receptor.
abstract: The bioactive lysophospholipids lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) have diverse effects on the developing nervous system and neural progenitors, but the molecular basis for their pleiotropic effects is poorly understood. We previously defined LPA and S1P signaling in proliferating human neural progenitor (hNP) cells, and the current study investigates their role in neuronal differentiation of these cells. Differentiation in the presence of LPA or S1P significantly enhanced cell survival and decreased expression of neuronal markers. Further, the LPA receptor antagonist Ki16425 fully blocked the effects of LPA, and differentiation in the presence of Ki16425 dramatically enhanced neurite length. LPA and S1P robustly activated Erk, but surprisingly both strongly suppressed Akt activation. Ki16425 and pertussis toxin blocked LPA activation of Erk but not LPA inhibition of Akt, suggesting distinct receptor and G-protein subtypes mediate these effects. Finally, we explored cross talk between lysophospholipid signaling and the cytokine leukemia inhibitory factor (LIF). LPA/S1P effects on neuronal differentiation were amplified in the presence of LIF. Similarly, the ability of LPA/S1P to regulate Erk and Akt was impacted by the presence of LIF; LIF enhanced the inhibitory effect of LPA/S1P on Akt phosphorylation, while LIF blunted the activation of Erk by LPA/S1P. Taken together, our results suggest that LPA and S1P enhance survival and inhibit neuronal differentiation of hNP cells, and LPA1 is critical for the effect of LPA. The pleiotropic effects of LPA may reflect differences in receptor subtype expression or cross talk with LIF receptor signaling.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Callihan
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
authors.forename: Mourad W
authors.initials: MW
authors.lastname: Ali
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Salazar
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA.
authors.forename: Nhat
authors.initials: N
authors.lastname: Quach
authors.affiliation: Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Stice
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA shooks@uga.edu.
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Hooks
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007555:Isoxazoles; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008246:Lysophospholipids; C520403:NUDT6 protein, rat; D011422:Propionates; D012333:RNA, Messenger; C060506:sphingosine 1-phosphate; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt; D048748:MAP Kinase Kinase Kinase 3; D013110:Sphingosine
keywords: Akt; Erk; Ki16425; LIF; LPA1; bFGF; lysophosphatidic acid; neural progenitor; neuronal differentiation; sphingosine 1-phosphate