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 LPA1–6, 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 LPA2, LPA5 and LPA6 receptors. We show that LPA-induced chemorepulsion is mediated specifically by the alkyl-LPA-preferring LPA5 receptor (GPR92), which raises intracellular cAMP via a noncanonical pathway. Our results define LPA5 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.
Highlights
Lysophosphatidic acid (LPA) is a multifunctional lipid mediator that stimulates migration, proliferation, survival and other functions in many different cell types, both normal and malignant
We show that the inhibitory effect of LPA is mediated by the LPA5 receptor and that a rise in cyclic AMP (cAMP) with consequent activation of protein kinase A (PKA) is an important effector of LPA5mediated chemorepulsion, with a possible additional role for reduced phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling
When testing various tumor cell types for their chemotactic response to 1-oleoyl-LPA (LPA(18:1)) and serum (FCS) in transwell assays, we found that B16F10 melanoma cell migration is strongly inhibited by both fetal calf serum (FCS) and LPA(18:1) (Figure 1A,B)
Summary
Lysophosphatidic acid (LPA) is a multifunctional lipid mediator that stimulates migration, proliferation, survival and other functions in many different cell types, both normal and malignant. LPA acts through six known G protein-coupled receptors (GPCRs), termed LPA1–6, which show both overlapping and distinct signaling properties and tissue distributions [1,2]. LPA-induced migration is primarily mediated by Edg-family LPA1 and LPA2 receptors and involves both Gi- and G12/13-mediated signaling pathways. We show that the inhibitory effect of LPA is mediated by the LPA5 receptor and that a rise in cAMP with consequent activation of protein kinase A (PKA) is an important effector of LPA5mediated chemorepulsion, with a possible additional role for reduced phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling. Our results identify LPA5 as an anti-migratory receptor and they point to a mechanism of LPA-induced chemorepulsion likely to be relevant for tumor cells that predominantly express LPA5, acting to override positive chemotactic signals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
