title: Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.
abstract: 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.
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. vivek.raai@nyumc.org
authors.forename: Vivek
authors.initials: V
authors.lastname: Rai
authors.forename: Fatouma
authors.initials: F
authors.lastname: Touré
authors.forename: Seth
authors.initials: S
authors.lastname: Chitayat
authors.forename: Renjun
authors.initials: R
authors.lastname: Pei
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhang
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C530105:Ccnd1 protein, mouse; D008246:Lysophospholipids; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; C032881:lysophosphatidic acid