Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad e...

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Bibliographic Details
Published in:The Journal of experimental medicine 2012-12, Vol.209 (13), p.2339-2350
Main Authors: Rai, Vivek, Touré, Fatouma, Chitayat, Seth, Pei, Renjun, Song, Fei, Li, Qing, Zhang, Jinghua, Rosario, Rosa, Ramasamy, Ravichandran, Chazin, Walter J, Schmidt, Ann Marie
Format: Article
Language:English
Subjects:
Animals
Brief Definitive Report
Cell Line, Tumor
Cyclin D1 - metabolism
Female
Humans
Lysophospholipids - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muscle, Smooth, Vascular - metabolism
Neoplasms - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Rats
Receptor for Advanced Glycation End Products
Receptors, Immunologic - deficiency
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Signal Transduction
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Summary:The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20120873