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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)

Bottom Line: Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential.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.

View Article: PubMed Central - HTML - PubMed

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

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.

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RAGE activates ERK in RH-7777 in rat hepatoma cells. (A) Real-time PCR for LPA receptors 1–5 and RAGE mRNA transcripts was performed in RH-7777 cells and normalized to 18s transcript levels. The graphs show relative fold of LPA receptor transcripts in RH-7777 cells. Assays were performed in triplicate and results shown are representative of two independent experiments. (B) Quantified levels of phosphorylated/total ERK are shown in RH-7777 rat hepatoma cells transfected with control vector, full-length RAGE, and upon 10 µM LPA stimulation at the indicated times. Representative results from triplicate experiments and at least two independent experiments are shown. *, P < 0.05. Error bars represent SD.
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fig3: RAGE activates ERK in RH-7777 in rat hepatoma cells. (A) Real-time PCR for LPA receptors 1–5 and RAGE mRNA transcripts was performed in RH-7777 cells and normalized to 18s transcript levels. The graphs show relative fold of LPA receptor transcripts in RH-7777 cells. Assays were performed in triplicate and results shown are representative of two independent experiments. (B) Quantified levels of phosphorylated/total ERK are shown in RH-7777 rat hepatoma cells transfected with control vector, full-length RAGE, and upon 10 µM LPA stimulation at the indicated times. Representative results from triplicate experiments and at least two independent experiments are shown. *, P < 0.05. Error bars represent SD.

Mentions: In addition, we tested RH7777 cells, as these cells are devoid of most LPA receptors (Valentine et al., 2008). As shown in Fig. 3 A only LPA2, LPA5, and RAGE, but not LPA1, LPA3, or LPA4 are expressed in these cells as shown by quantitative real-time PCR. When we overexpressed full-length RAGE in these cells, we found that stimulation with LPA resulted in a significantly higher degree of ERK phosphorylation compared with treatment of control or vector control-transfected cells (Fig. 3 B). Hence, in the presence of only two non-RAGE LPA receptors (LPA2 and LPA5), overexpression of RAGE augmented LPA-dependent signaling.


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)

RAGE activates ERK in RH-7777 in rat hepatoma cells. (A) Real-time PCR for LPA receptors 1–5 and RAGE mRNA transcripts was performed in RH-7777 cells and normalized to 18s transcript levels. The graphs show relative fold of LPA receptor transcripts in RH-7777 cells. Assays were performed in triplicate and results shown are representative of two independent experiments. (B) Quantified levels of phosphorylated/total ERK are shown in RH-7777 rat hepatoma cells transfected with control vector, full-length RAGE, and upon 10 µM LPA stimulation at the indicated times. Representative results from triplicate experiments and at least two independent experiments are shown. *, P < 0.05. Error bars represent SD.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526353&req=5

fig3: RAGE activates ERK in RH-7777 in rat hepatoma cells. (A) Real-time PCR for LPA receptors 1–5 and RAGE mRNA transcripts was performed in RH-7777 cells and normalized to 18s transcript levels. The graphs show relative fold of LPA receptor transcripts in RH-7777 cells. Assays were performed in triplicate and results shown are representative of two independent experiments. (B) Quantified levels of phosphorylated/total ERK are shown in RH-7777 rat hepatoma cells transfected with control vector, full-length RAGE, and upon 10 µM LPA stimulation at the indicated times. Representative results from triplicate experiments and at least two independent experiments are shown. *, P < 0.05. Error bars represent SD.
Mentions: In addition, we tested RH7777 cells, as these cells are devoid of most LPA receptors (Valentine et al., 2008). As shown in Fig. 3 A only LPA2, LPA5, and RAGE, but not LPA1, LPA3, or LPA4 are expressed in these cells as shown by quantitative real-time PCR. When we overexpressed full-length RAGE in these cells, we found that stimulation with LPA resulted in a significantly higher degree of ERK phosphorylation compared with treatment of control or vector control-transfected cells (Fig. 3 B). Hence, in the presence of only two non-RAGE LPA receptors (LPA2 and LPA5), overexpression of RAGE augmented LPA-dependent signaling.

Bottom Line: Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential.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.

View Article: PubMed Central - HTML - PubMed

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

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.

Show MeSH
Related in: MedlinePlus