輸送体間相互作用と発現変動の網羅的解析による輸送機能クロストークの予測基盤の構築

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 25136714
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Osaka University
• Principal Investigator: 永森 收志 大阪大学, 医学(系)研究科(研究院), 准教授 (90467572)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: トランスポーター / チャネル / 複合体 / 膜タンパク質 / プロテオーム

Outline of Annual Research Achievements

輸送体間物理的相互作用の網羅的解析により輸送体超複合体を同定し、加えて膜タンパク質の網羅的発現変動解析により輸送体の共変動情報を得て、両者をin silico上皮輸送モデル構築のための基盤情報として統合することで、輸送機能間のクロストークの予測を目指した。輸送体は独立して輸送機能を発揮するだけでなく、足場タンパク質などを含む超複合体を形成し、そのなかで相互に機能共役して高次の輸送機能を実現する。しかし研究代表者はこれまでの研究で、輸送機能に於いて関係を持たない輸送体同士の相互作用を見いだした。これは、直接の機能共役が想定されない輸送体間にも物理的相互作用に基づく細胞膜上での共安定化等を介した輸送機能間のクロストークが生じる可能性を示している。本研究では、小分子上皮輸送モデルのさらなる最適化に貢献する目的で、これまで明らかにした輸送体間の直接的な機能共役に基づく輸送機能間相互作用に加え、直接的な機能共役によらない、物理的相互作用を介した機能クロストークの予測を可能とする基盤情報の取得を進めた。
平成２６年度は、プロテオミクスを用いた輸送体超複合体の探索と構成因子の同定およびその定量的解析を行った。さらに多数の培養細胞株を対象に網羅的比較定量解析を行い、輸送体へ発現量に関しての網羅的な情報を取得し、小分子輸送機能と各輸送体分子の貢献率を明らかにした。また、領域内共同研究を進め、これまで解析を進めていなかった組織や臓器における輸送体の網羅的発現情報の獲得に成功した。さらに、その中から新しい輸送体超複合体を見出し、輸送体調複合体の生理機能解析を行った。これまで取得した網羅的情報をもとに、上皮における輸送体の相互作用情報および発現変動情報をまとめ、研究を総括した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Development of a Widely Usable Amino Acid Tracer: 76Br-α-Methyl-Phenylalanine for Tumor PET Imaging. (2015)
  • Author(s): Hanaoka H, Ohshima Y, Suzuki Y, Yamaguchi A, Watanabe S, Uehara T, Nagamori S, Kanai Y, Ishioka NS, Tsushima Y, Endo K, Arano Y.
  • Journal Title: J Nucl Med. Volume: in press
  • Peer Reviewed
• [Journal Article] Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB(0,+) , LAT1 and LAT2. (2015)
  • Author(s): Wongthai P, Hagiwara K, Miyoshi Y, Wiriyasermkul P, Wei L, Ohgaki R, Kato I, Hamase K, Nagamori S, Kanai Y.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 3 Pages: 279-86
  • DOI: 10.1111/cas.12602
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. (2015)
  • Author(s): Chiba T, Matsuo H, Kawamura Y, Nagamori S, Nishiyama T, Wei L, Nakayama A, Nakamura T, Sakiyama M, Takada T, Taketani Y, Suma S, Naito M, Oda T, Kumagai H, Moriyama Y, Ichida K, Shimizu T, Kanai Y, Shinomiya N.
  • Journal Title: Arthritis Rheumatol. Volume: 67(1) Issue: 1 Pages: 281-287
  • DOI: 10.1002/art.38884
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathological significance of ASC amino acid transporter-2 expression in pancreatic ductal carcinoma. (2015)
  • Author(s): Kaira K, Sunose Y, Arakawa K, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Oyama T, Takeyoshi I.
  • Journal Title: Histopathology. Volume: 66 Issue: 2 Pages: 234-43
  • DOI: 10.1111/his.12464
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] プロテオミクスを用いたトランスポーターの網羅的発現変動解析 (2015)
  • Author(s): 永森收志、金井好克
  • Journal Title: 遺伝: 生物の科学 Volume: 69 Pages: 47-51
• [Journal Article] Expression of amino acid transporters (LAT1, ASCT2 and xCT) as clinical significance in hepatocellular carcinoma. (2014)
  • Author(s): Namikawa M, Kakizaki S, Kaira K, Tojima H, Yamazaki Y, Horiguchi N, Sato K, Oriuchi N, Tominaga H, Sunose Y, Nagamori S, Kanai Y, Oyama T, Takeyoshi I, Yamada M.
  • Journal Title: Hepatol Res. Volume: in press Issue: 9 Pages: 1014-1022
  • DOI: 10.1111/hepr.12431
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of L-type amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. (2014)
  • Author(s): Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Oyama T, Asao T, Matsumoto M, Sawamura M.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 11 Pages: 1496-502
  • DOI: 10.1111/cas.12529
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] [Amino acid transporters in cancer] (2014)
  • Author(s): Nagamori S, Kanai Y.
  • Journal Title: Seikagaku Volume: 86 Pages: 338-44
• [Journal Article] CD98 as a novel prognostic indicator for patients with stage III/IV hypopharyngeal squamous cell carcinoma. (2014)
  • Author(s): Toyoda M, Kaira K, Shino M, Sakakura K, Takahashi K, Takayasu Y, Tominaga H, Oriuchi N, Nikkuni O, Suzuki M, Iijima M, Tsukamoto N, Nagamori S, Kanai Y, Oyama T, Chikamatsu K.
  • Journal Title: Head Neck. Volume: in press Issue: 11 Pages: 1-6
  • DOI: 10.1002/hed.23797
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. (2014)
  • Author(s): Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, Takayasu Y, Takahashi K, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Oyama T, Chikamatsu K.
  • Journal Title: Br J Cancer. Volume: 110 Issue: 10 Pages: 2506-13
  • DOI: 10.1038/bjc.2014.178
  • Peer Reviewed / Open Access
• [Journal Article] Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP) (2014)
  • Author(s): Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T
  • Journal Title: Hepatology Volume: 59 Issue: 5 Pages: 1726-1737
  • DOI: 10.1002/hep.26982
  • Peer Reviewed
• [Journal Article] Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. (2014)
  • Author(s): Toyoda M, Kaira K, Ohshima Y, Ishioka NS, Shino M, Sakakura K, Takayasu Y, Takahashi K, Tominaga H, Oriuchi N, Nagamori S, Kanai Y, Oyama T, Chikamatsu
  • Journal Title: Br J Cancer Volume: in press
  • Peer Reviewed
• [Journal Article] ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer (2014)
  • Author(s): Shimizu K, Kaira K, Tomizawa Y, Sunaga N, Kawashima O, Oriuchi N, Tominaga H, Nagamori S, Kanai Y, Yamada M, Oyama T, Takeyoshi I
  • Journal Title: Br J Cancer Volume: Epub Issue: 8 Pages: 2030-2039
  • DOI: 10.1038/bjc.2014.88
  • Peer Reviewed / Open Access
• [Journal Article] Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A (2014)
  • Author(s): Matsuzaki S, Enomoto T, Serada S, Yoshino K, Nagamori S, Morimoto A, Yokoyama T, Kim A, Kimura T, Ueda Y, Fujita M, Fujimoto M, Kanai Y, Kimura T, Naka T
  • Journal Title: Int J Cancer Volume: 134 Issue: 8 Pages: 1796-1809
  • DOI: 10.1002/ijc.28526
  • Peer Reviewed / Open Access
• [Journal Article] Nicotine induces dendritic spine remodeling in cultured hippocampal neurons. (2014)
  • Author(s): Oda A^1, Yamagata K, Nakagomi S, Uejima H, Wiriyasermkul P, Ohgaki R, Nagamori S, Kanai Y, Tanaka H.
  • Journal Title: J Neurochem. Volume: 128(2) Issue: 2 Pages: 246-255
  • DOI: 10.1111/jnc.12470
  • Peer Reviewed
• [Journal Article] Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer (2013)
  • Author(s): Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I
  • Journal Title: BMC Cancer Volume: 16 Issue: 1 Pages: 482-482
  • DOI: 10.1186/1471-2407-13-482
  • Peer Reviewed
• [Journal Article] Biological evaluation of 3-[18F]fluoro-α-methyl-D-tyrosine (D-[18F]FAMT) as a novel amino acid tracer for positron emission tomography. (2013)
  • Author(s): Ohshima Y
  • Journal Title: Ann Nucl Med Volume: 27 Issue: 4 Pages: 314-324
  • DOI: 10.1007/s12149-013-0687-7
  • Peer Reviewed
• [Presentation] トランスポーターの網羅的プロテオミクスによるアミノ酸輸送系のプロファイリングと変動解析 (2015)
  • Author(s): 永森收志
  • Organizer: 第19回アミノ酸セミナー
  • Place of Presentation: 東京
  • Year and Date: 2015-12-05
  • Invited
• [Presentation] アミノ酸トランスポーターを標的とした創薬研究から見えてきた 標的分子の新たな機能 (2015)
  • Author(s): 永森收志
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-17
  • Invited
• [Presentation] Interaction of a novel SGLT2 inhibitor Canagliglozin with human SGLT2 (2015)
  • Author(s): Ling Wei, 大垣 隆一, 永森 收志, 金井 好克
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-05-22
• [Presentation] LAT1 reveals multiplephysiological functions of LAT1 and mechanism of anti-tumor activity by LAT1 inhibitors. (2015)
  • Author(s): Nagamori S and Kanai Y
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-20
  • Invited
• [Presentation] 膜輸送複合体transportsome における輸送機能共役の解析 (2015)
  • Author(s): 永森收志、大垣隆一、金井好克
  • Organizer: 第2回生体界面研究会
  • Place of Presentation: 大阪
  • Year and Date: 2015-02-20
• [Presentation] Expression Profiles of Amino Acid Transporters in Cancer Cell Lines by Comprehensive Quantitative Proteomics (2015)
  • Author(s): Noriyoshi Isozumi、Pattama Wiriyaserkul、Pornparn Kongpracha、Shushi Nagamori、Yoshikatsu Kanai
  • Organizer: 新学術領域研究「多階層生体機能学」終了記念シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2015-02-05
• [Presentation] Transportsomes; the physical and/or functional complexes of transporters (2014)
  • Author(s): Nagamori S
  • Organizer: The 2nd International Symposium on Epithelial Barrier and Transport
  • Place of Presentation: 滋賀
  • Year and Date: 2014-11-01
  • Invited
• [Presentation] 網羅的定量プロテオミクス解析によるがん細胞株のトランスポーター発現プロファイル (2014)
  • Author(s): Noriyoshi Isozumi、Pattama Wiriyaserkul、Pornparn Kongpracha、Shushi Nagamori、Yoshikatsu Kanai
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-17
• [Presentation] Functions and roles of amino acid transporters. (2014)
  • Author(s): Nagamori S
  • Organizer: The 2nd International Conference of D-Amino Acid Research
  • Place of Presentation: 宇都宮
  • Year and Date: 2014-09-03
  • Invited
• [Presentation] Amino acid transporters in cancer (2014)
  • Author(s): Nagamori S and Kanai Y
  • Organizer: The 2nd Awaji International Workshop on “Electron Spin Science & Technology: Biological and Materials Science Oriented Applications”
  • Place of Presentation: 淡路島
  • Year and Date: 2014-06-17
  • Invited
• [Presentation] Study of a cellular signaling network stimulated with leucine transported by a cancer-type amino acid transporter LAT1. (2014)
  • Author(s): Pornparn Kongprach, Pattama Wiriyasermkul, Noriyoshi Isozumi, Printip Wongthai, Suguru Okuda, Kenjiro Tadagaki, Ryuichi Ohgaki, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 第61回日本生化学会近畿支部会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-17
• [Presentation] Transport of 3-fluoro-L-α-methyltyrosine (FAMT) by amino acid transports and organic ion transporters explains cancer-specificity and renal background in 18F-FAMT PET (2014)
  • Author(s): Ling Wei, 富永 英之, Pattama Wiriyasermkul, 大垣 隆一, 萩原 浩平, 永森 收志, 金井 好克
  • Organizer: 5th Asia Pacific ISSX Meeting 2014
  • Place of Presentation: 天津、中国
  • Year and Date: 2014-05-10
• [Presentation] A novel cystine transporter in S3 segment of the renal proximal tubule is an “unknown-partner” of Slc3a1 (rBAT). (2013)
  • Author(s): Shushi Nagamori, Pattama Wiriyasermkul, Meritxell Espino Guarch, Kazuhisa Okuyama, Saya Nakagomi, Kenijiro Tadagaki, Kazuaki Takafuji, Ryuichi Ohgaki, Manuel Palacín, Yoshikatsu Kanai
  • Organizer: 2nd HDP international symposium on Multi-Level Systems Biology
  • Place of Presentation: Tokyo
• [Presentation] Functional coupling of transporters in a complex
  • Author(s): Shushi Nagamori
  • Organizer: First Awaji International Workshop on “Electron Spin Science & Technology: Biological and Materials Science Oriented Applications”
  • Place of Presentation: Awaji, Hyogo
  • Invited
• [Presentation] がん細胞のアミノ酸トランスポーター
  • Author(s): 永森收志、金井好克
  • Organizer: 第31回日本ヒト細胞学会学術集会
  • Place of Presentation: 所沢
  • Invited
• [Presentation] Metabolomics and proteomics analyses of knockout mice reveal real physiological substrates of an organic anion transporter
  • Author(s): Shushi Nagamori
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 膜輸送複合体におけるトランスポーターの機能共役
  • Author(s): 永森收志
  • Organizer: 第4回難治疾患共同研究拠点シンポジウム
  • Place of Presentation: 御茶ノ水
  • Invited
• [Presentation] アミノ酸トランスポーターと細胞内アミノ酸シグナリング
  • Author(s): 永森 收志
  • Organizer: 生理学研究所研究会「細胞センサーの分子機構・相互関連・ネットワーク研究会」
  • Place of Presentation: 岡崎
  • Invited
• [Presentation] Functional coupling of a urate-anion exchanger URAT1 and Na+-dependent anion transporter SMCT2 on a PDZK1 scaffold; Proposal of “Transportsome” for urate-transport
  • Author(s): Shushi Nagamori
  • Organizer: The 58th Annual Meeting of the Biophysical Society
  • Place of Presentation: San Francisco、USA
• [Presentation] 網羅的定量オミクスによるトランスポーター研究の新しい展開Comprehensive and quantitative "omics" bring up new world of transporter research.
  • Author(s): 永森收志
  • Organizer: 2014年度日本農芸化学会
  • Place of Presentation: 東京
  • Invited