LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor

PLoS One. 2011;6(12):e29260. doi: 10.1371/journal.pone.0029260. Epub 2011 Dec 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Polarity / drug effects
  • Cell Proliferation / drug effects
  • Chemotaxis / drug effects
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HeLa Cells
  • Humans
  • Lysophospholipids / pharmacology*
  • Melanoma, Experimental / enzymology
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology*
  • Mice
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoric Diester Hydrolases / pharmacology
  • Polylysine / pharmacology
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Serum
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Transfection
  • alpha-MSH / pharmacology


  • Lysophospholipids
  • Phosphatidylinositol Phosphates
  • Receptors, Lysophosphatidic Acid
  • phosphatidylinositol 3,4,5-triphosphate
  • Polylysine
  • sphingosine 1-phosphate
  • alpha-MSH
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Sphingosine
  • lysophosphatidic acid