Control of vascular barrier integrity by MTM family of phosphatidylinositol 3-phosphate phosphatase

• Project/Area Number: 25670162
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: TAKUWA Yoh 金沢大学, 医学系, 教授 (60171592)
• Co-Investigator(Renkei-kenkyūsha): YOSHIOKA Kazuaki 金沢大学, 医学系, 助教 (80333368)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ホスホイノシチド / ホスファターゼ / PI3-キナーゼ / 小胞 / 血管 / 内皮 / イノシトールリン脂質 / PI3キナーゼ / フォスファターゼ

Outline of Final Research Achievements

We studied phosphatidylinositol 3-phosphate (PI-3-P) phosphatase in vascular endothelial cells. Among 14 isoforms of MTM family members, we identified one isoform which was relatively abundantly expressed in endothelial cells. Fluorescent imaging showed the expression of GFP-tagged phosphatase in endosomes. The phosphatase negatively regulated cellular PI-3-P level and was involved in the regulation of endosomal movement. The PI-3-P phosphatase controlled migration, cell-cell adhesion and morphogenesis of endothelial cells through regulating PI-3-P level.

Research Products

• [Journal Article] Phosphatidylinositol 3-kinase Class II α-Isoform PI3K-C2α Is Required for Transforming Growth Factor β-induced Smad Signaling in Endothelial Cells. (2015)
  • Author(s): Aki S, Yoshioka K, Okamoto Y, Takuwa N, Takuwa Y.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 10 Pages: 6086-6105
  • DOI: 10.1074/jbc.m114.601484
  • NAID: 120005593954
  • Peer Reviewed / Open Access
• [Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells. (2014)
  • Author(s): Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T
  • Journal Title: Diabetologia Volume: 57 Issue: 9 Pages: 1968-1976
  • DOI: 10.1007/s00125-014-3306-9
  • NAID: 120005463349
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of S1P1 receptor pathway in angiogenic effects of a novel adenosine-like nucleic acid analog COA-Cl in cultured human vascular endothelial cells (2014)
  • Author(s): Igarashi J, Hashimoto T, Kubota Y, Shoji K, Maruyama T, Sakakibara N, TakuwaY, Ujihara Y, Katanosaka Y, Mohri S, Naruse K, Yamashita T, Okamoto R, Hirano K, Kosaka H, Takata M, Konishi R, Tsukamoto I.
  • Journal Title: Pharmacology Research & Perspectives Volume: 2 Issue: 5 Pages: 68-68
  • DOI: 10.1002/prp2.68
  • Peer Reviewed / Open Access
• [Journal Article] Receptor for advanced glycation end products - membrane type1 matrix metalloprotease axis regulates tissue factor expression via RhoA and Rac1 activation in high-mobility group box-1 stimulated endothelial Cells. (2014)
  • Author(s): Sugimoto K, Ohkawara H, Takuwa Y, Ishibashi T and Takeishi Y .
  • Journal Title: PLoS One. Volume: 9 Issue: 12 Pages: 1-13
  • DOI: 10.1371/journal.pone.0114429
  • Peer Reviewed / Open Access
• [Journal Article] スフィンゴシン-1-リン酸の炎症における多彩な役割 (2014)
  • Author(s): 多久和 陽
  • Journal Title: 実験医学 Volume: 32 Pages: 138-146
• [Journal Article] Sphingosine-1-Phosphate Signaling and Cardiac Fibrosis. (2013)
  • Author(s): Takuwa N, Okamoto Y, Yoshioka K, Takuwa Y.
  • Journal Title: Inflammation and Regeneration Volume: 33 Pages: 96-108
  • NAID: 130004943837
  • Peer Reviewed
• [Journal Article] CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations. (2013)
  • Author(s): Hara A, Sakai N, Furuichi K, Sakai Y, Takeya M, Bucala R, Mukaida N, Takuwa Y, Matsushima K, Kaneko S, Wada T.
  • Journal Title: Clin Exp Nephrol. Volume: 17 Issue: 6 Pages: 793-804
  • DOI: 10.1007/s10157-013-0796-6
  • Peer Reviewed
• [Journal Article] Sphingosine-1-phosphate receptor-2 protects against anaphylactic shock through suppression of eNOS in mice. (2013)
  • Author(s): Cui H, Okamoto Y, Yoshioka K, et al.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 132 Issue: 5 Pages: 1205-1214
  • DOI: 10.1016/j.jaci.2013.07.026
  • Peer Reviewed
• [Presentation] Sphingosine 1-phosphate receptor-2 plays a protective role against lipopolysaccharide (LPS)-induced acute lung injury (2015)
  • Author(s): Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Sho Aki, JuanJuan Zhao, Hoa Quynh Pham, Md. Azadul Kabir Sarker, Saori Koizumi, Yoh Takuwa
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場・展示場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Essential role of PI3K class II α for endosomal signaling of S1P1 and other receptors (2015)
  • Author(s): Yoh Takuwa
  • Organizer: 6th international conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: 京王プラザホテル
  • Year and Date: 2015-02-10 – 2015-02-12
  • Invited
• [Presentation] クラスIIα型PI3K-C2αはALK5 内在化及び足場タンパクSARA のエンドソームへの動員を制御しTGF-1-Smad2/3 を介した血管新生を調節する (2014)
  • Author(s): 安藝 翔、吉岡 和晃、岡本 安雄、多久和 典子、多久和 陽
  • Organizer: 第56回 日本脂質生化学会
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2014-06-06 – 2014-06-07
• [Presentation] Sphingosine-1-phosphate receptor-2 (S1P2) negatively regulates eNOS and protects against acute vascular barrier disruption (2014)
  • Author(s): Yasuo Okamoto, Cui Hong, Kazuaki Yoshioka, Noriko Takuwa, Toshishige Shibamoto, Yoh Takuwa
  • Organizer: The 18th International Vascular Biology Meeting 2014 (IVBM 2014)
  • Place of Presentation: みやこめっせ
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Distinct role of S1P2 in the functional regulation of vascular endothelium and smooth muscle (2014)
  • Author(s): Yoh Takuwa, Yasuo Okamoto, Kazuaki Yoshioka, Noriko Takuwa
  • Organizer: The 18th International Vascular Biology Meeting 2014 (IVBM 2014)
  • Place of Presentation: みやこめっせ
  • Year and Date: 2014-04-14 – 2014-04-17
  • Invited
• [Presentation] Sphingosine-1-phosphate receptor-2 protects against anaphylactic shock through inhibiting eNOS (2014)
  • Author(s): Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Juanjuan Zhao, Yoh Takuwa
  • Organizer: 第91回日本生理学会大会 Symposium “Mechanisms on distributive shock and other blood pressure control failures”
  • Place of Presentation: 鹿児島大学 郡元キャンパス（鹿児島県鹿児島市）
  • Invited
• [Presentation] クラスII 型PI3K-C2αはメンブレン・トラフィック調節を介して血管バリア機能を制御する (2014)
  • Author(s): 吉岡 和晃，岡本 安雄，多久和 典子，多久和 陽
  • Organizer: 第91回日本生理学会大会 シンポジウム「心血管系の形態・機能研究の最前線」
  • Place of Presentation: 鹿児島大学 郡元キャンパス（鹿児島県鹿児島市）
  • Invited
• [Presentation] S1P2は内皮型一酸化窒素合成酵素を抑制することによりアナフラキシーショックに対して防御的に働く (2013)
  • Author(s): 岡本 安雄 崔 弘 吉岡 和晃 多久和 典子 多久和 陽
  • Organizer: 第55回日本脂質生化学会
  • Place of Presentation: ホテル松島大観荘(宮城県宮城郡)
• [Presentation] Phosphatidylinositol 3-kinase classII α-isoform contols vesicular trafficking in endothelial cells to serve the essential role in angiogenesis and vascular barrier integrity (2013)
  • Author(s): Yoh Takuwa
  • Organizer: 第45回動脈硬化学会
  • Place of Presentation: 京王プラザホテル(東京都新宿区）
  • Invited
• [Presentation] Sphingosine-1-phosphate receptor-2 negatively regulates eNOS and protects against acute vascular barrier disruption (2013)
  • Author(s): Yoh Takuwa
  • Organizer: 2013FASEB Summer Research Conference Lysophospholipid and Other Related Mediators - From Bench to Clinic
  • Place of Presentation: Hilton Niseko Village（北海道虻田郡）
  • Invited
• [Presentation] S1P受容体はeNOS-NO経路を抑制することによりアナフラキシーショックに対して抑制的に働く (2013)
  • Author(s): 岡本安雄、崔弘、吉岡和晃、多久和典子、多久和陽
  • Organizer: 第21回日本血管生物医学会
  • Place of Presentation: 千里阪急ホテル（大阪府豊中市）
• [Presentation] TGFβ1-Smad2/3シグナル伝達系を介した血管新生調節におけるクラスIIαPI3キナーゼPI3K-C2αの機能的役割 (2013)
  • Author(s): 安藝 翔、吉岡 和晃、多久和 典子、岡本 安雄、多久和 陽
  • Organizer: 第21回日本血管生物医学会
  • Place of Presentation: 千里阪急ホテル（大阪府豊中市）
• [Presentation] クラスIIα型PI3キナーゼ-C2αによる血管新生・バリア機能調節メカニズム (2013)
  • Author(s): 吉岡 和晃、多久和 典子、岡本 安雄、多久和 陽
  • Organizer: 第21回日本血管生物医学会 シンポジウム「血管機能を抑制するシグナリング機構」
  • Place of Presentation: 千里阪急ホテル（大阪府豊中市）
  • Invited
• [Presentation] クラスII 型PI3K-C2αはSARA のエンドソームへの動員を制御しTGFß1-Smad2/3シグナル伝達系を介した血管新生を調節する (2013)
  • Author(s): 安藝 翔，吉岡 和晃，岡本 安雄，多久和 典子，多久和 陽
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場/神戸国際展示場/神戸ポートピアホテル（兵庫県神戸市）
• [Book] サイトカイン・増殖因子キーワード (2015)
  • Author(s): 宮園浩平 他
  • Total Pages: 420
  • Publisher: 羊土社
• [Remarks] 血管分子生理学教室（旧生理学第一講座） 金沢大学大学院 医学系研究科 循環医科学専攻
  • URL: http://physiology1.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学情報リポジトリ
  • URL: http://dspace.lib.kanazawa-u.ac.jp/dspace/
• [Remarks] 血管分子生理学教室（旧生理学第一講座） 金沢大学大学院 医学系研究科 循環医科学専攻
  • URL: http://physiology1.w3.kanazawa-u.ac.jp/