Identification of a novel GPCR for oxidized LDL and its role in development of arteriosclerosis.

• Project/Area Number: 22659013
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: AOKI Junken 東北大学, 大学院・薬学研究科, 教授 (20250219)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,090,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: 酸化リン脂質 / Gタンパク質共役型受容体 / GPCR / 酸化LDL / リゾホスファチジン酸 / 受容体 / 産生酵素 / ノックアウトマウス

Research Abstract

We identified a novel orphan GPCR that reacted specifically with oxidized phospholipids. In this study we further perform biochemical characterization of the GPCR including precise ligand specificity. In addition, we also examine the patho-physiological roles of the GPCR, especially in the development of arteriosclerosis.

Research Products

• [Journal Article] Synthetic biotinylated peptide compounds derived from Asp-hemolysin : Novel potent inhibitors of platelet-activating factor (2012)
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  • Journal Title: Eur J Pharmacol
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• [Journal Article] Simultaneous quantitation of sphingoid bases and their phosphates in biological samples by liquid chromatography / electrospray ionizationtandem mass spectrometry (2012)
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• [Journal Article] The β9 loop domain of PA-PLA1α has a crucial role in autosomal recessive woolly hair/hypotrichosis. (2012)
  • Author(s): Shinkuma S, Inoue A, Aoki J, Nishie W, Natsuga K, Ujiie H, Nomura T, Abe R, Akiyama M, Shimizu H
  • Journal Title: J Invest Dermatol. Volume: (印刷中) Pages: 2093-2095
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• [Journal Article] The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells (2012)
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  • Journal Title: J Clin Invest. Volume: (In press)(未定) Pages: 1416-1426
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• [Journal Article] GPR34 is a receptor for lysophosphatidylserine with a fatty acid at the sn-2 position. (2012)
  • Author(s): Kitamura H, Makide K, Shuto A, Ikubo M, Inoue A, Suzuki K, Sato Y, Nakamura S, Otani Y, Ohwada T, Aoki J
  • Journal Title: J. Biochemistry Volume: 151 Pages: 511-518
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  • NAID: 10031166091
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• [Journal Article] A 3D view of autotaxin (2012)
  • Author(s): Nishimasu H, Ishitani R, Aoki J, Nureki O
  • Journal Title: Trends Pharmacol Sci. Volume: 33 Pages: 138-145
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• [Journal Article] Aoki J. Surface loops of extracellular phospholipase A(1)determine both substrate specificity and preference for lysophospholipids (2012)
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  • Journal Title: J.Lipid Res. Volume: 53 Pages: 513-521
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• [Journal Article] Regulation of peroxisomal lipid metabolism by the catalytic activity of the tumor suppressor H-rev107 (2012)
  • Author(s): Uyama T, Ichi I, Kono N, Inoue A, Tsuboi K, Jin XH, Araki N, Aoki J, Arai H, Ueda N
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 2706-2718
  • DOI: 10.1074/jbc.m111.267575
  • Peer Reviewed
• [Journal Article] Identification and biochemical characterization of a novel autotaxin isoform, ATXδ, with a four-amino acid deletion (2012)
  • Author(s): Hashimoto T, Okudaira S, Igarashi K, Hama K, Yatomi Y, Aoki J
  • Journal Title: J Biochem. Volume: 151 Pages: 89-97
  • DOI: 10.1093/jb/mvr126
  • NAID: 10031166046
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• [Journal Article] Autotaxin regulates vascular development via multiple lysophosphatidic acid (LPA) receptors in zebrafish. (2011)
  • Author(s): Yukiura H, Hama K, Nakanaga K, Tanaka M, Asaoka Y, Okudaira S, Arima N, Inoue A, Hashimoto T, Arai H, Kawahara A, Nishina H, Aoki J
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 43972-43983
  • DOI: 10.1074/jbc.m111.301093
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• [Journal Article] LPA-producing enzyme PA-PLA鼠ヨア regulates hair follicle development by modulating EGFR signalling. (2011)
  • Author(s): Inoue A., Arima N., et al
  • Journal Title: EMBO J. Volume: vol.30 Pages: 4248-4260
  • DOI: 10.1038/emboj.2011.296
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• [Journal Article] Serum autotaxin measurements in pregnant women: application for the differentiation of normal pregnancy and pregnancy-induced hypertension (2011)
  • Author(s): Masuda A, Fujii T, Iwasawa Y, Nakamura K, Ohkawa R, Igarashi K, Okudaira S, Ikeda H, Kozuma S, Aoki J, Yatomi Y
  • Journal Title: Clin Chim Acta Volume: 412 Pages: 1944-1950
  • DOI: 10.1016/j.cca.2011.06.039
  • Peer Reviewed
• [Journal Article] Autotaxin regulates vascular development via multiple lysophosphatidic acid (LPA) receptorsFluorescence probe forlysophospholipase C/NPP6 activity and a potent NPP6 inhibitor (2011)
  • Author(s): Mitsuyasu Kawaguchi, Takayoshi Okabe, Shinichi, Okudaira, Kenjiro Hanaoka, Yuuta Fujikawa, Takuya Terai, Toru Komatsu, Hirotatsu Kojima, Junken Aoki, Tetsuo Nagano
  • Journal Title: J Am Chem Soc. Volume: 133 Pages: 12021-12030
  • DOI: 10.1021/ja201028t
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• [Journal Article] Specific increase in serum autotaxin activity in patients with pancreatic cancer (2011)
  • Author(s): Nakai Y, Ikeda H, Nakamura K, Kume Y, Fujishiro M, Sasahira N, Hirano K, Isayama H, Tada M, Kawabe T, Komatsu Y, Omata M, Aoki J, Koike K, Yatomi Y
  • Journal Title: Clin Biochem Volume: 44 Pages: 576-581
  • DOI: 10.1016/j.clinbiochem.2011.03.128
  • Peer Reviewed
• [Journal Article] Autotaxin as a novel serum marker of liver fibrosis (2011)
  • Author(s): Nakagawa H, Ikeda H, Nakamura K, Ohkawa R, Masuzaki R, Tateishi R, Yoshida H, Watanabe N, Tejima K, Kume Y, Iwai T, Suzuki A, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Omata M, Igarashi K, Aoki J, Koike K, Yatomi Y
  • Journal Title: Clin Chim Acta Volume: 412 Pages: 1201-1206
  • DOI: 10.1016/j.cca.2011.03.014
  • Peer Reviewed
• [Journal Article] Crystal structure of Autotaxin, a secreted lysophospholipase D that generates GPCR-signaling lipid mediator (2011)
  • Author(s): Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O
  • Journal Title: Nature Struct. Mol. Biol. Volume: 18 Pages: 205-212
  • DOI: 10.1038/nsmb.1998
  • Peer Reviewed
• [Journal Article] Immunohistochemical detection of autotaxin (ATX)/lysophospholipase D (lysoPLD)in submucosal invasive colorectal cancer (2011)
  • Author(s): Kazama S, Kitayama J, Aoki J, Mori K, Nagawa H.
  • Journal Title: J Gastrointest Cancer Volume: 42 Pages: 204-211
  • Peer Reviewed
• [Journal Article] Autotaxin and lysophosphatidic acid1 receptor-mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine (2010)
  • Author(s): Nagai J, Uchida H, Matsushita Y, Yano R, Ueda M, Niwa M, Aoki J, Chun J, Ueda H
  • Journal Title: Mol Pain Volume: 6 Pages: 78-78
  • DOI: 10.1186/1744-8069-6-78
  • Peer Reviewed
• [Journal Article] Development of an activity-based probe for autotaxin (2010)
  • Author(s): Cavalli S, Houben AJ, Albers HM, van Tilburg EW, de Ru A, Aoki J, van Veelen P, Moolenaar WH, Ovaa H
  • Journal Title: Chembiochem Volume: 11 Pages: 2311-2317
  • DOI: 10.1002/cbic.201000349
  • Peer Reviewed
• [Journal Article] Autotaxin controls caudal diencephalon-mesencephalon development in the chick (2010)
  • Author(s): Ohuchi H, Fukui H, Matsuyo A, Tomonari S, Tanaka M, Arai H, Noji S, Aoki J
  • Journal Title: Dev Dyn Volume: 239 Pages: 2647-2658
  • DOI: 10.1002/dvdy.22403
  • Peer Reviewed
• [Journal Article] Expression of phosphatidylserine-specific phospholipase A(1)mRNA in human THP-1-derived macrophages (2010)
  • Author(s): Hosono H, Homma M, Ogasawara Y, Makide K, Aoki J, Niwata H, Watanabe M, Inoue K, Ohkohchi N, Kohda Y
  • Journal Title: Cell Transplant Volume: 19 Pages: 759-64
  • Peer Reviewed
• [Journal Article] Glucagon regulates intracellular distribution of adipose differentiation-related protein during triacylglycerol accumulation in the liver (2010)
  • Author(s): Takahashi K, Sasabe N, Ohshima K, Kitazato K, Kato R, Masuda Y, Tsurumaki M, Obama T, Okudaira S, Aoki J, Arai H, Yamaguchi T, Itabe H
  • Journal Title: J Lipid Res Volume: 51 Pages: 2571-80
  • DOI: 10.1194/jlr.m004648
  • Peer Reviewed
• [Journal Article] Autotaxin-an LPA producing enzyme with diverse functions (2010)
  • Author(s): Nakanaga K, Hama K, Aoki J
  • Journal Title: J Biochem Volume: 148 Pages: 13-24
  • DOI: 10.1093/jb/mvq052
  • NAID: 10027876904
  • Peer Reviewed
• [Journal Article] Biological roles of lysophosphatidic acid signaling through its production by autotaxin (2010)
  • Author(s): Okudaira S, Yukiura H, Aoki J
  • Journal Title: Biochimie Volume: 92 Pages: 698-706
  • DOI: 10.1016/j.biochi.2010.04.015
  • Peer Reviewed
• [Journal Article] A novel enzyme immunoassay for the determination of phosphatidylserine-specific phospholipase A(1)in human serum samples (2010)
  • Author(s): Nakamura K, Igarashi K, Ohkawa R, Saiki N, Nagasaki M, Uno K, Hayashi N, Sawada T, Syukuya K, Yokota H, Arai H, Ikeda H, Aoki J, Yatomi Y
  • Journal Title: Clin Chim Acta Volume: 411 Pages: 1090-1094
  • DOI: 10.1016/j.cca.2010.04.006
  • Peer Reviewed
• [Journal Article] Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts (2010)
  • Author(s): David M, Wannecq E, Descotes F, Jansen S, Deux B, Ribeiro J, Serre CM, Gres S, Bendriss-Vermare N, Bollen M, Saez S, Aoki J, Saulnier-Blache JS, Clezardin P, Peyruchaud O
  • Journal Title: PLoS One Volume: 17
  • DOI: 10.1371/journal.pone.0009741
  • Peer Reviewed
• [Journal Article] LPA(3), a unique G protein-coupled receptor for lysophosphatidic acid (2010)
  • Author(s): Hama K, Aoki J
  • Journal Title: Prog Lipid Res Volume: 49 Pages: 335-342
  • DOI: 10.1016/j.plipres.2010.03.001
  • Peer Reviewed
• [Journal Article] Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis (2010)
  • Author(s): Shinkuma S, Akiyama M, Inoue A, Aoki J, Natsuga K, Nomura T, Arita K, Abe R, Ito K, Nakamura H, Ujiie H, Shibaki A, Suga H, Tsunemi Y, Nishie W, Shimizu H
  • Journal Title: Hum Mutat Volume: 31 Pages: 602-10
  • DOI: 10.1002/humu.21235
  • Peer Reviewed
• [Journal Article] Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain (2010)
  • Author(s): Ma L, Uchida H, Nagai J, Inoue M, Aoki J, Ueda H
  • Journal Title: J Pharmacol Exp Ther Volume: 333 Pages: 540-546
  • DOI: 10.1124/jpet.109.164830
  • Peer Reviewed
• [Journal Article] Adiponectin suppresses tumorigenesis in Apc(Min)(/+)mice (2010)
  • Author(s): Otani K, Kitayama J, Yasuda K, Nio Y, Iwabu M, Okudaira S, Aoki J, Yamauchi T, Kadowaki T, Nagawa H
  • Journal Title: Cancer Lett Volume: 288 Pages: 177-82
  • DOI: 10.1016/j.canlet.2009.06.037
  • Peer Reviewed
• [Presentation] 酸化リン脂質に応答する新規受容体の同定 (2012)
  • Author(s): 石黒純
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] Ectodomain shedding of TGFα as a versatile readout for GPCR activation (2012)
  • Author(s): Asuka Inoue, 他
  • Organizer: Keystone Symposia G Protein-Coupled Receptors : Molecular Mechanisms and Novel Functional Insights
  • Place of Presentation: Banff, Canada
  • Year and Date: 2012-02-17
• [Presentation] Development and characterization of TGFalpha shedding assay : a novel and powerful method to detect G12/13 signaling (2012)
  • Author(s): Jun Ishiguro, 他
  • Organizer: Keystone Symposia G Protein-Coupled Receptors : Molecular Mechanisms and Novel Functional Insights
  • Place of Presentation: Banff, Canada
  • Year and Date: 2012-02-17
• [Presentation] 生理活性リゾリン脂質の定量系の開発と産生機構の解析 (2011)
  • Author(s): 井上飛鳥, 他
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] 新規GPCRシグナル検出法～TGFalpha切断アッセイ～の開発 (2011)
  • Author(s): 石黒純, 他
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-21
• [Presentation] Autotaxin regulates vascular development via multiple LPA receptors in zebrafish (2011)
  • Author(s): Junken Aoki
  • Organizer: 2011 FASEB Summer Research Conference
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2011-08-15
• [Presentation] TGF-alpha ectodomain shedding underlies LPA-induced hair formation (2011)
  • Author(s): Asuka Inoue, 他
  • Organizer: 2011 FASEB Summer Research Conference
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2011-08-14
• [Presentation] Mechanism of extracellular production of bioactive lysophospholipids using a newly developed LC-MS/MS method (2011)
  • Author(s): Asuka Inoue, 他
  • Organizer: LIPID MAPS Annual Meeting 2011
  • Place of Presentation: San Diego, USA
  • Year and Date: 2011-05-02
• [Presentation] TGFα切断アッセイを用いたオーファンGPCRのリガンドスクリーニング (2010)
  • Author(s): 石黒純
  • Organizer: 第9回次世代を担う若手ファーマ・バイオフ_オーラム2010
  • Place of Presentation: 京都、京都大学大学院薬学研究科
  • Year and Date: 2010-10-02
• [Presentation] Lysophosphatidic acid plays a critical role in hair follicle formation through TGF.-alpha release and EGFR transactivation (2010)
  • Author(s): 井上飛鳥
  • Organizer: The 27th Naito Conference on Menmbrane Dynamics and Lipid Biology[I]
  • Place of Presentation: Sapporo,CHATERAISE Gateaux Kingdom SAPPORO
  • Year and Date: 2010-06-29
• [Presentation] TGFα切断アッセイによるGPCRシグナルの検出 (2010)
  • Author(s): 石黒純
  • Organizer: 第52回日本脂質生化学会
  • Place of Presentation: 群馬、秋森旅館
  • Year and Date: 2010-06-15
• [Presentation] Autotaxin and LPA Signaling in Cardiovascular Development (2010)
  • Author(s): Junken Aoki
  • Organizer: Keystone Symposia
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-06-08
• [Presentation] Lysophosphatidic acid plays a critical role in hair follicle formation through TGFa release and EGFR transactivation (2010)
  • Author(s): 井上飛鳥
  • Organizer: Keystone Symposia Bioactive Lipids : Biochemistry and Diseases(D2)
  • Place of Presentation: Kyoto, Westin Miyako Kyoto
  • Year and Date: 2010-06-07
• [Presentation] TGFα切断アッセイによるG12/13シグナルの検出 (2010)
  • Author(s): 石黒純
  • Organizer: 第7回GPCR研究会
  • Place of Presentation: 東京、日本科学未来館 みらいCANホール
  • Year and Date: 2010-05-07
• [Presentation] 新規GPCRシグナル検出法-TGFα切断アッセイ・の開発 (2010)
  • Author(s): 石黒純
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡、静岡県コンベンションアーツセンター
  • Year and Date: 2010-03-28
• [Remarks]
  • URL: http://www.pharm.tohoku.ac.jp/~seika/H21/index.html
• [Remarks]
  • URL: http://www.pharm.tohoku.ac.jp/~seika/H21/index.html
• [Patent(Industrial Property Rights)] オートタキシンアイソフォーム特異的抗体および検出方法 (2011)
  • Inventor(s): 青木淳賢、五十嵐浩二
  • Industrial Property Rights Holder: 株式会社東ソー、東北大学
  • Industrial Property Number: 2011-150054
  • Filing Date: 2011-07-06
  • Application Year: 2011
• [Patent(Industrial Property Rights)] 自己免疫疾患治療薬のスクリーニング方法 (2011)
  • Inventor(s): 青木淳賢、巻出久美子、井上飛鳥、大和田智彦、井久保仁也、尾谷優子
  • Industrial Property Rights Holder: 東北大学、東京大学
  • Industrial Property Number: 2011-112881
  • Filing Date: 2011-05-29
  • Application Year: 2011
• [Patent(Industrial Property Rights)] ホスファチジルセリン特異的ホスホリパーゼA1測定による全身性エリテマトーデスの検査方法および検査薬 (2010)
  • Inventor(s): 沢田哲治、矢冨裕、中村和宏、青木淳賢、五十嵐浩二
  • Industrial Property Rights Holder: 株式会社東ソー、東京大学、東北大学
  • Industrial Property Number: 2010-172068
  • Filing Date: 2010-07-30
  • Application Year: 2010