title: LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor.
abstract: Lysophosphatidic acid (LPA), a lipid mediator enriched in serum, stimulates cell migration, proliferation and other functions in many cell types. LPA acts on six known G protein-coupled receptors, termed LPA(1-6), showing both overlapping and distinct signaling properties. Here we show that, unexpectedly, LPA and serum almost completely inhibit the transwell migration of B16 melanoma cells, with alkyl-LPA(18:1) being 10-fold more potent than acyl-LPA(18:1). The anti-migratory response to LPA is highly polarized and dependent on protein kinase A (PKA) but not Rho kinase activity; it is associated with a rapid increase in intracellular cAMP levels and PIP3 depletion from the plasma membrane. B16 cells express LPA(2), LPA(5) and LPA(6) receptors. We show that LPA-induced chemorepulsion is mediated specifically by the alkyl-LPA-preferring LPA(5) receptor (GPR92), which raises intracellular cAMP via a noncanonical pathway. Our results define LPA(5) as an anti-migratory receptor and they implicate the cAMP-PKA pathway, along with reduced PIP3 signaling, as an effector of chemorepulsion in B16 melanoma cells.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Jongsma
authors.forename: Elisa
authors.initials: E
authors.lastname: Matas-Rico
authors.forename: Adrian
authors.initials: A
authors.lastname: Rzadkowski
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology; D011107:Polylysine / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D044967:Serum; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D000521:alpha-MSH / Q000494:pharmacology; D000099189:Lysophospholipase D
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D008246:Lysophospholipids; D018129:Phosphatidylinositol Phosphates; D010727:Phosphoric Diester Hydrolases; D011107:Polylysine; D049368:Receptors, Lysophosphatidic Acid; D013110:Sphingosine; D000521:alpha-MSH; D000099189:Lysophospholipase D; C060974:phosphatidylinositol 3,4,5-triphosphate; C060506:sphingosine 1-phosphate; C032881:lysophosphatidic acid