Study on the regulation of endothelial cell-cell adhesions by Rap1 small GTPase and its biological functions

• Project/Area Number: 19770185
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Cell biology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: FUKUHARA Shigetomo National Cardiovascular Center Research Institute, 循環器形態部, 室長 (70332880)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,840,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥540,000); Fiscal Year 2008: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2007: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: 細胞内 / 細胞間情報伝達 / VE-cadherin / 細胞間接着 / Rap1 / アクチン細胞骨格 / FRAP解析 / 細胞内小胞輸送

Research Abstract

全身の細胞に酸素や栄養を供給する血管の内腔は、血管内皮細胞によって覆われている。内皮細胞は互いに接着し血液が外に漏れないようにバリヤーとして機能しているが、炎症時や虚血によって新たに血管が形成されるときにはそのバリヤー機能は低下する。本研究では血管のバリヤー機能を制御するメカニズムを解明するため、内皮細胞間の接着を制御するVascular Endothelial(VE)-Cadherinに注目し、その接着活性を調節するシグナル伝達系を解析した。その結果、Rap1低分子量G蛋白質がアクチン細胞骨格系を制御することによりVE-cadherin接着を増強することが明らかになった。

Research Products

• [Journal Article] Tie2 is tied at the cell-cell contacts and to extracellular matrix by Angiopoietin-1. (2009)
  • Author(s): S. Fukuhara, K. Sako, K. Noda, K. Nagao, K. Miura, N. Mochizuki
  • Journal Title: Exp. Mol. Med 41 Pages: 133-139
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 induces Kruppel-Like Factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. (2009)
  • Author(s): K. Sako, S. Fukuhara, M. Takashi, T. Hamakubo, H. Song, T. Kodama, A. Fukamizu, J. S. Gutkind, G. Y. Koh, N. Mochizuki
  • Journal Title: J. Biol. Chem 284 Pages: 5592-5601
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 induces Kruppel-Like Factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. (2009)
  • Author(s): K. Sako
  • Journal Title: J. Biol. Chem. 284 Pages: 5592-5601
  • Peer Reviewed
• [Journal Article] Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. (2008)
  • Author(s): S. Fukuhara, K. Sako, T. Minami, K. Noda, H. Z. Kim, T. Kodama, M. Shibuya, N. Takakura, G. Y. Koh, N. Mochizuki
  • Journal Title: Nat. Cell Biol 10 Pages: 513-526
  • Peer Reviewed
• [Journal Article] Cryptide signaling: amphiphilic peptide-induced exocytosis mechanisms in mast cells. (2008)
  • Author(s): H. Mukai, M. Kikuchi, S. Fukuhara, Y. Kiso, E. Munekata
  • Journal Title: Biochem. Biophys. Res. Commun 375 Pages: 22-26
  • Peer Reviewed
• [Journal Article] Single common mutation in the cardiac sodium channel gene SCN5A with diverse clinical phenotypes. (2008)
  • Author(s): N. Makita, E. Behr, W. Shimizu, M. Horie, A. Sunami, L. Crotti, E. Schulze-Bahr, S. Fukuhara, N. Mochizuki, T. Makiyama, H. Itoh, M. Christiansen, P. McKeown, K. Miyamoto, S. Kamakura, H. Tsutsui, P. J. Schwartz, A. L. George Jr, D. M. Roden.
  • Journal Title: J. Clin. Invest 118 Pages: 2219-2229
  • Peer Reviewed
• [Journal Article] Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation. (2008)
  • Author(s): N. Yasuda, S. Miura, H. Akazawa, T. Tanaka, Y Qin, Y. Kiya, S. Imaizumi, M. Fujino, K. Ito, Y. Zou, J. Ge, S. Fukuhara, S. Kunimoto, N. Mochizuki, K. Fukuzaki, T. Sato, H. Nakaya, K. Saku, I. Komuro
  • Journal Title: EMBO Rep 9 Pages: 179-186
  • Peer Reviewed
• [Journal Article] Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. (2008)
  • Author(s): S. Fukuhara
  • Journal Title: Nat. Cell Biol. 10 Pages: 513-526
  • Peer Reviewed
• [Journal Article] Cryptide signaling : amphiphilic peptide-induced exocytosis mechanisms in mast cells. (2008)
  • Author(s): H. Mukai
  • Journal Title: Biochem. Biophys. Res. Commun. 375 Pages: 22-26
  • Peer Reviewed
• [Journal Article] Single common mutation in the cardiac sodium channel gene SCN5A with diverse clinical phenotypes. (2008)
  • Author(s): N. Makita
  • Journal Title: J. Clin. Invest. 118 Pages: 2219-2229
  • Peer Reviewed
• [Journal Article] Conformational switch of angiotensin II type 1 receptor underlying mechanical stressinduced activation. (2008)
  • Author(s): N. Yasuda
  • Journal Title: EMBO Rep 9 Pages: 179-186
  • Peer Reviewed
• [Journal Article] Protein Tyrosine Kinase 2β as a Candidate Gene for Hypertension. (2007)
  • Author(s): K. Kamide, Y. Kokubo, S. Fukuhara, H. Hanada, J. Yang, A. Kada, J. Nagura, S. Takiuchi, T. Horio, Y. Kawano, A. Okayama, H. Tomoike, T. Miyata
  • Journal Title: Pharmacogenet. Genomics 17 Pages: 931-939
  • Peer Reviewed
• [Journal Article] ・-defensin overexpression induces progressive muscle degeneration in mice. (2007)
  • Author(s): Y. Yamaguchi, T. Nagase, T. Tomita, K. Nakamura, S. Fukuhara, T. Amano, H. Yamamoto, Y. Ide, M. Suzuki, S. Teramoto, T. Asano, K. Kangawa, N. Nakagata, Y. Ouchi, H. Kurihara
  • Journal Title: Am. J. Physiol. Cell Physiol 292
  • Peer Reviewed
• [Journal Article] Protein Tyrosine Kinase 2β as a Candidate Gene for Hypertension (2007)
  • Author(s): K. Kamide
  • Journal Title: Pharmacogenet.Genomics. 17 Pages: 931-939
  • Peer Reviewed
• [Journal Article] □-defensin over expression induces progressive mucle degeneration in mice (2007)
  • Author(s): Y. Yamaguchi
  • Journal Title: J.Physiol.Cell Physiol. 292
  • Peer Reviewed
• [Journal Article] Tie2 is tied at the cell-cell contacts and to extracellular matrix by Angiopoietin-1.
  • Author(s): S. Fukuhara
  • Journal Title: Exp. Mol. Biol. (In press)
  • Peer Reviewed
• [Journal Article] Differential function of Tie2 at cell-cell colltacts and cen-substratum contacts regulated by angiopoietin-1
  • Author(s): S. Fukuhara
  • Journal Title: Nat.Cell Biol. in press
  • Peer Reviewed
• [Journal Article] Single common mutation in the cardiac sodium channel gene SCN5A with diverse clinical phenotypes
  • Author(s): N. Makita
  • Journal Title: J. Clip, Invest. in press
  • Peer Reviewed
• [Presentation] Angiostasis and angiogenesis regulated by angiopoietin-1/Tie2 receptor system (2009)
  • Author(s): Shigetomo Fukuhara
  • Organizer: Japan-Mexico Workshop
  • Place of Presentation: Mexico city, Mexico
  • Year and Date: 2009-02-25
• [Presentation] アンジオポエチン-1/Tie2 受容体シグナルの空間的・機能的制御 (2009)
  • Author(s): 福原茂朋
  • Organizer: 第5回宮崎サイエンスキャンプ
  • Place of Presentation: フェニックスシーガイアリゾート宮崎
  • Year and Date: 2009-02-20
• [Presentation] アンジオポエチン-1/Tie2受容体シグナルの空間的・機能的制御 (2009)
  • Author(s): 福原 茂朋
  • Organizer: 第5回宮崎サイエンスキャンプ
  • Place of Presentation: フェニックスシーガイアリゾート宮崎
  • Year and Date: 2009-02-20
• [Presentation] ANGIOSTASIS AND ANGIOGENESIS REGULATED BY ANGIOPOIETIN-1/TIE2 RECEPTOR SYSTEM (2009)
  • Author(s): S. Fukuhara
  • Organizer: Japan-Mexico Workshop
  • Place of Presentation: Mexico city, Mexico
  • Year and Date: 2009-02-02
• [Presentation] Angiostasis and angiogenesis regulated by angiopoietin1-Tie2 signaling (2008)
  • Author(s): Shigetomo Fukuhara
  • Organizer: The 6th Korea-Japan Joint Symposium on Vascular Biology & The 16th Annual Meeting of the Japanese Vascular Biology and Medicine Organization
  • Place of Presentation: 金沢市石川県立音楽堂
  • Year and Date: 2008-12-05
• [Presentation] アンジオポエチン-1/Tie2 受容体シグナルによる血管安定化・血管新生制御機構 (2008)
  • Author(s): 福原茂朋
  • Organizer: 生理研研究会「イオンチャネル・トランスポーターと心血管機能 : 学際的取り組みによる新戦略」
  • Place of Presentation: 岡崎市自然科学研究機構 岡崎コンファレンスセンター
  • Year and Date: 2008-11-20
• [Presentation] アンジオポエチン-1/Tie2受容体シグナルによる血管安定化・血管新生制御機構 (2008)
  • Author(s): 福原 茂朋
  • Organizer: 生理研研究会「イオンチャネル・トランスポーターと心血管機能 : 学際的取り組みによる新戦略」
  • Place of Presentation: 岡崎市自然科学研究機構岡崎コンファレンスセンター
  • Year and Date: 2008-11-20
• [Presentation] Angiostatic and Angiogenic Regulation by Intercellular Trans-associated Tie2 and ECM-anchored Tie2 (2008)
  • Author(s): Shigetomo Fukuhara
  • Organizer: 67th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] Angiopoietin-1 Regulates Distinct Signaling Functions through Trans-associated Tie2 at Cell-cell Contacts and Extracellular Matrix-anchored Tie2 at Cell-substratum Contacts (2008)
  • Author(s): Shigetomo Fukuhara
  • Organizer: 15th International Vascular Biology Meeting
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2008-06-05
• [Presentation] アンジオポエチン-1によって活性化されたTie2 受容体は細胞間および細胞-基質間接着部位に移動し異なったシグナルを活性化する (2007)
  • Author(s): 福原茂朋
  • Organizer: 第30回日本分子生物学会、第80回日本生化学会合同年会
  • Place of Presentation: 横浜パシフィコ横浜
  • Year and Date: 2007-12-12
• [Presentation] アンジオポエチンー1によって活性化されたTie2受容体は細胞間および細胞-基質間接着部位に移動し異なったシグナルを活性化する (2007)
  • Author(s): 福原 茂朋
  • Organizer: 第30回日本分子生物学会、第80回日本生化学会合同年会
  • Place of Presentation: 横浜パシフィコ横浜
  • Year and Date: 2007-12-12
• [Presentation] アンジオポエチン-1/Tie2 受容体シグナルの空間的制御とその血管形成における役割 (2007)
  • Author(s): 福原茂朋
  • Organizer: 第11回Molecular Cardiovascular Conference
  • Place of Presentation: 北海道キロロリゾート
  • Year and Date: 2007-09-16
• [Presentation] アンジオポエチンー1によって活性化されたTie2受容体は細胞間および細胞-基質問接着部位に移動し異なったシグナルを活性化する (2007)
  • Author(s): 福原 茂朋
  • Organizer: 第11回 Molecular Cardiovascular Conference
  • Place of Presentation: 北海道キロロリゾート
  • Year and Date: 2007-09-16
• [Book] 実験医学(Current Topics) (2008)
  • Author(s): 福原茂朋、望月直樹
  • Publisher: 羊土社
• [Book] 実験医学 増刊(生細胞を使ったライブイメージングでみえる生命現象) (2008)
  • Author(s): 福原茂朋、望月直樹
  • Publisher: 羊土社
• [Book] 循環器病研究の進歩 (2008)
  • Author(s): 福原茂朋、望月直樹
  • Publisher: 協和企画
• [Book] 実験医学(Current Topics) (2008)
  • Author(s): 福原 茂朋
  • Publisher: 羊土社
• [Book] 実験医学増刊(生細胞を使ったライブイメージングでみえる生命現象) (2008)
  • Author(s): 福原 茂朋
  • Publisher: 羊土社
• [Book] 循環器病研究の進歩(Angiopoietin-Tie2によるangiostasisとangiogenesis制御) (2008)
  • Author(s): 福原 茂朋
  • Publisher: 協和企画
• [Remarks] 本研究課題によって得られた研究成果が、2008年4月21日、日経新聞および2008年4月21日、朝日新聞地方版夕刊で紹介された。