Biological role of the proton-sensing G-protein coupled receptor TDAG8

• Project/Area Number: 20590305
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: ISHII Satoshi The University of Tokyo, 大学院・医学系研究科, 教授 (10300815)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: LLC細胞 / プロトンセンサー / 癌 / フーロトンセンサー / 破骨細胞 / 骨代謝

Research Abstract

T cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor. In this study, we show that TDAG8-overexpressing mouse Lewis lung carcinoma (LLC) cells enhance tumor development in animal models. The exogenously expressed TDAG8 rendered LLC cells resistant to acidic culture conditions by PKA and ERK in vitro. Provided that TDAG8 is overexpressed in various tumors and tumor cell lines, our data suggest that TDAG8 enhances tumorigenesis by linking tumor-induced acidity to tumor cell survival/proliferation.

Research Products

• [Journal Article] LPA_4 regulates blood and lymphatic vessel formation during mouse embryogenesis. (2010)
  • Author(s): Sumida H, Noguchi K, Kihara Y, Abe M, Yanagida K, Hamano F, Sato S, Tamaki K, Morishita Y, Kano MR., Iwata C, Miyazono K, Sakimura K, Shimizu T, Ishii S
  • Journal Title: Blood 116 Pages: 5060-5070
  • Peer Reviewed
• [Journal Article] The G protein-coupled receptor TDAG8 facilitates tumor development by serving as an extracellular pH sensor. (2010)
  • Author(s): Ihara Y, Kihara Y, Hamano F, Yanagida K, Morishita Y, Kunita A, Yamori T, Fukayama M, Aburatani H, Shimizu T, Ishii S
  • Journal Title: Proc Natl Acad Sci USA 107(Direct submission) Pages: 17309-17314
  • Peer Reviewed
• [Journal Article] Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. (2010)
  • Author(s): Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T
  • Journal Title: Nature 464 Pages: 1313-1319
  • Peer Reviewed
• [Journal Article] Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain. (2010)
  • Author(s): Hasegawa S, Kohro Y, Shiratori M, Ishii S, Shimizu T, Tsuda M, Inoue K
  • Journal Title: PLoS One 5
  • Peer Reviewed
• [Journal Article] The leukotriene B(4) receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis. (2010)
  • Author(s): Kihara Y, Yokomizo T, Kunita A, Morishita Y, Fukayama M, Ishii S, Shimizu T
  • Journal Title: Biochem.Biophys.Res.Commun. 394 Pages: 673-678
  • Peer Reviewed
• [Journal Article] The leukotriene B(4) receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis. (2010)
  • Author(s): Kihara, Y., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 394 Pages: 673-678
  • Peer Reviewed
• [Journal Article] Adiponectin and AdipoRl regulate PGC-lalpha and mitochondria by Ca(2+) and AMPK/SIRT 1. (2010)
  • Author(s): Iwabu, M., et al.
  • Journal Title: Nature Volume: 464 Pages: 1313-1319
  • Peer Reviewed
• [Journal Article] Role of PAF receptor in proinflammatory cytokine expression in thedorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain. (2010)
  • Author(s): Hasegawa, S., et al.
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] The G protein-coupled receptor T-cell death-associated gene 8(TDAG8) facilitates tumor development by serving as an extracellular pH sensor. (2010)
  • Author(s): Ihara, Y., et al.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. Volume: 107 Pages: 17309-17314
  • Peer Reviewed
• [Journal Article] LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. (2010)
  • Author(s): Sumida, H., et al.
  • Journal Title: Blood Volume: 116 Pages: 5060-5070
  • Peer Reviewed
• [Journal Article] Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. (2009)
  • Author(s): Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J-i, Ishii S, Shimizu T
  • Journal Title: Proc Natl Acad Sci USA 106(Direct submission) Pages: 21807-21812
  • Peer Reviewed
• [Journal Article] A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss. (2009)
  • Author(s): Hikiji H, Ishii S, Yokomizo T, Takato T, Shimizu T
  • Journal Title: Proc Natl Acad Sci USA 106(Direct submission) Pages: 21294-21299
  • Peer Reviewed
• [Journal Article] Non-Edg family lysophosphatidic acid (LPA) receptors. (2009)
  • Author(s): Ishii S, Noguchi K, Yanagida K
  • Journal Title: Prostaglandins Other Lipid Mediat 89(Invited Review) Pages: 57-65
  • Peer Reviewed
• [Journal Article] Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6. (2009)
  • Author(s): Yanagida K, Masago K, Nakanishi H, Kihara Y, Hamano F, Tajima Y, Taguchi R, Shimizu T, Ishii S
  • Journal Title: J Biol Chem 284 Pages: 17731-17741
  • Peer Reviewed
• [Journal Article] Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of proinflammatory cytokine production in peritoneal macrophages. (2009)
  • Author(s): Mogi C, Tobo M, Tomura H, Murata N, He XD, Sato K, Kimura T, Ishizuka T, Sasaki T, Sato T, Kihara Y, Ishii S, Harada A, Okajima F
  • Journal Title: J Immunol 182 Pages: 3243-3251
  • Peer Reviewed
• [Journal Article] Opposing effects of platelet-activating factor and lyso-platelet activating factor on neutrophil and platelet activation. (2009)
  • Author(s): Welch EJ, Naikawadi RP, Li Z, Lin, P, Ishii S, Shimizu T, Tiruppathi C, Du X, Subbaiah PV, Ye RD
  • Journal Title: Mol Pharmacol 75 Pages: 227-234
  • Peer Reviewed
• [Journal Article] Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA_6 (2009)
  • Author(s): Yanagida, K., et al.
  • Journal Title: J.Biol.Chem. 284 Pages: 17731-17741
  • Peer Reviewed
• [Journal Article] Non-Edg family lysophosphatidic acid(LPA)receptors. (2009)
  • Author(s): Ishii, S., et al.
  • Journal Title: Prostaglandins Other Lipid Mediat. 89 Pages: 57-65
  • Peer Reviewed
• [Journal Article] A distinctive role of the leukotriene B_4 receptor BLT1 in osteoclastic activity during bone loss. (2009)
  • Author(s): Hikiji, H., et al.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 106 Pages: 21294-21299
  • Peer Reviewed
• [Journal Article] Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. (2009)
  • Author(s): Kihara, Y., et al.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 106 Pages: 21807-21812
  • Peer Reviewed
• [Journal Article] Opposing effects of platelet-activating factor and lyso-platelet activating factor on neutrophil and platelet activation. (2009)
  • Author(s): Welch, E.J. et al.
  • Journal Title: Mol. Pharmacol 75 Pages: 227-234
  • Peer Reviewed
• [Journal Article] Involvement of proton-sensing TDAG8 in extracellular acidification-induced inhibition of pro-in flammatory cytokine production in peritoneal macrophages. (2009)
  • Author(s): Mogi, C. et al.
  • Journal Title: J. Immunol. 182 Pages: 3243-3251
  • Peer Reviewed
• [Journal Article] Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport. (2008)
  • Author(s): Moos MPW, Mewburn JD, Kan FWK., Ishii S, Abe M, Sakimura K, Noguchi K, Shimizu T, Funk CD
  • Journal Title: FASEB J 22 Pages: 4352-4362
  • Peer Reviewed
• [Journal Article] Endothelial cysteinyl leukotriene 2 receptor (CysLT2R) expression mediates myocardial ischemia-reperfusion injury. (2008)
  • Author(s): Jiang W, Hall SR, Moos MPW, Cao RY, Ishii S, Ogunyankin KO, Melo LG, Funk CD
  • Journal Title: Am J Pathol 172 Pages: 592-602
  • Peer Reviewed
• [Journal Article] Endothelial cysteinyl leukotriene 2 receptor (CysLT2R) expression mediates myocardial ischemi a-reperfusion injury. (2008)
  • Author(s): Jiang, W. et al.
  • Journal Title: Am. J. Pathol 172 Pages: 592-602
  • Peer Reviewed
• [Journal Article] Platelet-activating factor production in the spinal cord of experimental allergic encephalomyeliti s mice via the aroup IVA cvtosolic PLA2-LvsoPAFAT axis. (2008)
  • Author(s): Kihara, Y. et al.
  • Journal Title: J. Immunol. 181 Pages: 5008-5014
  • Peer Reviewed
• [Journal Article] Cysteinyl leukotriene 2 receptor-mediated vascular permeability viatransendothelial vesicle tran sport. (2008)
  • Author(s): Moos, M. P. W. et al.
  • Journal Title: FASEB J. 22 Pages: 4352-4362
  • Peer Reviewed
• [Presentation] ヒト貧毛症の原因となるp2y5/LPA_6変異体の機能解析 (2010)
  • Author(s): 真砂佳代、柳田圭介、浜野文三江、清水孝雄、石井聡
  • Organizer: 第52回日本脂質生化学会シンポジウム
  • Place of Presentation: 群馬・伊香保
• [Presentation] ヒト貧毛症の原因となるp2y5/LPA_6変異体の機能解析 (2010)
  • Author(s): 真砂佳代、柳田圭介、浜野文三江、清水孝雄、石井聡(発表者)
  • Organizer: 第52回日本脂質生化学会
  • Place of Presentation: 群馬・伊香保
• [Presentation] 新規リゾリン脂質受容体の探索 (2009)
  • Author(s): 石井聡, 浜野文三江, 柳田圭介, 清水孝雄
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 兵庫県神戸ポートピアホテル
  • Year and Date: 2009-10-23
• [Presentation] Non-Edg family lysophosphatidic acid (LPA) receptors. (2009)
  • Author(s): Satoshi Ishii, Keisuke Yanagida, Hayakazu Sumida, Takao Shimizu
  • Organizer: FASEB Summer Research Conferences ; Lysophos pholipids and related lipids in biology and diseases.
  • Place of Presentation: Carefree Resort and Villas, Carefree, Arizona, USA
  • Year and Date: 2009-07-02
• [Presentation] 脂質メディエーターによる実験的アレルギー性脳脊髄炎の調節 (2009)
  • Author(s): 石井聡, 木原泰行, 北芳博, 清水孝雄
  • Organizer: 第21回日本アレルギー学会春季臨床大会
  • Place of Presentation: 岐阜県岐阜都ホテル
  • Year and Date: 2009-06-05
• [Presentation] 細胞外pH感知性G蛋白質共役型受容体TDAG8の癌の進展における役割 (2009)
  • Author(s): 石井聡
  • Organizer: 第3回炎症・脂質代謝・メタボリサーチフォーラム
  • Place of Presentation: 東京大学
  • Year and Date: 2009-01-31
• [Presentation] 新規リソリン脂質受容体の探索 (2009)
  • Author(s): 石井聡、浜野文三江、柳田圭介、清水孝雄
  • Organizer: 第82回日本生化学会大会シンポジウム
  • Place of Presentation: 神戸
• [Presentation] 脂質メディエーターによる実験的アレルギー性脳脊髄炎の調節 (2009)
  • Author(s): 石井聡、木原泰行、北芳博、清水孝雄
  • Organizer: 第21回日本アレルギー学会春季臨床大会シンポジウム
  • Place of Presentation: 岐阜
• [Presentation] Biological roles of Non-Edg family LPA receptors. FASEB Summer Research Conferences (2009)
  • Author(s): Ishii S,, Yanagida K, Sumida H, Shimizu T
  • Organizer: Lysophospholipids and related lipids in biology and diseases, Carefree
  • Place of Presentation: Arizona
• [Presentation] Non-Edg family lysophosphatidic acid (LPA) receptors. (2009)
  • Author(s): Ishii S, Yanagida K, Sumida H, Shimizu T
  • Organizer: 4th International Conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo (Japan)
• [Presentation] 非EDG型リゾホスファチジン酸受容体の生体機能 (2008)
  • Author(s): 石井聡
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会シンポジウム
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2008-12-09
• [Presentation] 脂質メディエーター受容体の病態機能一ベンチサイドからの呼吸器研究 (2008)
  • Author(s): 石井聡
  • Organizer: 第5回東京レスピレーションフロンティア
  • Place of Presentation: 東京・山の上ホテル
  • Year and Date: 2008-11-07
• [Presentation] 非EDG型リゾホスファチジン酸受容体の生体機能 (2008)
  • Author(s): 石井聡、柳田圭介、住田隼一、野口響子、木原泰行、浜野文三江、清水孝雄、阿部学、崎村建司
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会シンポジウム
  • Place of Presentation: 神戸
• [Remarks] プレスリリース
• [Remarks] 東京大学(2010年9月24日)
  • URL: http://www.u-toky0.ac.jp/public/pdf/220924_01.pdf
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• [Patent(Industrial Property Rights)] オートタキシン測定によるステロイド服用効果の検査方法 (2010)
  • Inventor(s): 石井聡,住田隼一,矢冨裕,中村和宏,佐藤伸一,門野岳史,五十嵐浩二
  • Industrial Property Rights Holder: 国立大学法人東京大学,東ソー株式会社
  • Industrial Property Number: 2010-136250
  • Filing Date: 2010-06-15