Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.

Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ, Schmidt AM
J Exp Med. 2012 209 (13): 2339-50

PMID: 23209312 · PMCID: PMC3526353 · DOI:10.1084/jem.20120873

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.

MeSH Terms (18)

Animals Cell Line, Tumor Cyclin D1 Female Humans Lysophospholipids Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Muscle, Smooth, Vascular Neoplasms Proto-Oncogene Proteins c-akt Rats Receptor for Advanced Glycation End Products Receptors, Immunologic Recombinant Proteins Signal Transduction

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