Identification and the physiological role of a cystine transporter

• Project/Area Number: 24591198
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Osaka University
• Principal Investigator: NAGAMORI Shushi 大阪大学, 医学(系)研究科(研究院), 准教授 (90467572)
• Co-Investigator(Kenkyū-buntansha): OHGAKI Ryuichi 大阪大学, 大学院医学系研究科, 助教 (20467525) ; NISHIZONO Hirofumi 富山大学, 生命科学先端研究センター, 助教 (10502289)
• Co-Investigator(Renkei-kenkyūsha): KANAI Yoshikatsu 大阪大学, 大学院医学系研究科, 教授 (60204533)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: シスチン尿症 / アミノ酸トランスポーター / 腎臓 / ヘテロダイマー / トランスポーター / アミノ酸 / ヘテロ二量体 / 再構成系 / 機能共役 / 膜複合体 / プロテオミクス

Outline of Final Research Achievements

The heterodimeric amino acids transporter (HAT) family, which consists of heavy chains (Slc3) and light chains (Slc7), has important roles for amino acid transports in many types of organs. Among the family, rBAT forms a heterodimeric complex only with b0,+AT. Mutations in the two genes cause cystinuria, an autosomal recessive disorder of renal reabsorption of cystine at the apical membranes of proximal tubules. However, the expression paradox of the proteins has been remaining. While rBAT highly express in the S3 segment of the proximal tubules, the expression of b0,+AT decrease from the S1 to the S3 segment. In this study, Slc7a13, one of the HAT family members with an unknown heavy chain, was found to form a heterodimer with rBAT. Slc7a13 was expressed dominantly in the S3 segment and transported cystine. These findings strongly indicate that Slc7a13 is the secondary cystine transporter at the S3 segment in the kidney, which was postulated the presence in 70’s.

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] 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] 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 Pages: 2506-13
  • Peer Reviewed
• [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] 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] YY1 binds to α-synuclein 3'-flanking region SNP and stimulates antisense noncoding RNA expression. (2013)
  • Author(s): Mizuta I, Takafuji K, Ando Y, Satake W, Kanagawa M, Kobayashi K, Nagamori S, Shinohara T, Ito C, Yamamoto M, Hattori N, Murata M, Kanai Y, Murayama S, Nakagawa M, Toda T.
  • Journal Title: J Hum Genet Volume: 58 Issue: 11 Pages: 711-719
  • DOI: 10.1038/jhg.2013.90
  • 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
• [Journal Article] Glycolipozyme MPIase is essential for topology inversion of SecG during preprotein translocation (2012)
  • Author(s): Moser, M., Nagamori, S., Huber, M., Tokuda, H., Nishiyama, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: (in press) Issue: 24 Pages: 9734-9739
  • DOI: 10.1073/pnas.1303160110
  • Peer Reviewed
• [Journal Article] NRFL-1, the C. elegans NHERF Orthologue, Interacts with Amino Acid Transporter 6 (AAT-6) for Age-Dependent Maintenance of AAT-6 on the Membrane. (2012)
  • Author(s): Kohei Hagiwara
  • Journal Title: Plos one Volume: 7(8) Issue: 8 Pages: e43050-e43050
  • DOI: 10.1371/journal.pone.0043050
  • Peer Reviewed
• [Journal Article] Establishment of Stable Cell Lines With High Expression of Heterodimers of Human 4F2hc and Human Amino Acid Transporter LAT1 or LAT2 and Delineation of Their Differential Interaction With <I>&alpha;</I>-Alkyl Moieties (2012)
  • Author(s): Narakorn Khunweeraphong
  • Journal Title: Journal of Pharmacological Sciences Volume: 119 Issue: 4 Pages: 368-380
  • DOI: 10.1254/jphs.12124FP
  • NAID: 10031071638
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Transport of 3-fluoro-L-α-methyl-tyrosine by tumor-upregulated L-type amino acid transporter 1: a cause of the tumor uptake in PET. (2012)
  • Author(s): Wiriyasermkul P, Nagamori S, Tominaga H, Oriuchi N, Kaira K, Nakao H, Kitashoji T, Ohgaki R, Tanaka H, Endou H, Endo K, Sakurai H, Kanai Y.
  • Journal Title: J Nucl Med. Volume: 53 Issue: 8 Pages: 1253-1261
  • DOI: 10.2967/jnumed.112.103069
  • Peer Reviewed
• [Journal Article] Linkage of N-cadherin to multiple cytoskeletal elements revealed by a proteomic approach in hippocampal neurons. (2012)
  • Author(s): Tanaka H, Takafuji K, Taguchi A, Wiriyasermkul P, Ohgaki R, Nagamori S, Suh PG, Kanai Y.
  • Journal Title: Neurochem Int. Volume: 61 Issue: 2 Pages: 240-250
  • DOI: 10.1016/j.neuint.2012.05.008
  • Peer Reviewed
• [Presentation] Nagamori S and Kanai Y, Identification of a new heterodimeric amino acid transporter in the apical membrane of renal proximal tubule. (2015)
  • Author(s): Nagamori S and Kanai Y
  • Organizer: 第120回 日本解剖学会総会･全国学術集会・第92回 日本生理学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-22
  • Invited
• [Presentation] A new cystine transporter in S3 segment of the renal proximal tubule is an “unknown-partner” of Slc3a1 (rBAT). (2015)
  • Author(s): Nagamori S.
  • Organizer: The final HD physiology Symposium
  • Place of Presentation: 大阪
  • Year and Date: 2015-03-06
• [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 (2014)
  • 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: 2014-12-05
  • Invited
• [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] 腎近位尿細管におけるアミノ酸輸送複合体の解析 (2014)
  • Author(s): 永森收志
  • Organizer: 2014年度生理研研究会「粘膜免疫学と膜輸送生理学の融合」
  • Place of Presentation: 岡崎
  • Year and Date: 2014-10-27
• [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 (2014)
  • 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: 2014-10-07
  • Invited
• [Presentation] 栄養とトランスポーター：アミノ酸の場合 (2014)
  • Author(s): 永森收志
  • Organizer: 第３４９回大阪大学臨床栄養研究会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-28
  • Invited
• [Presentation] A new cystine transporter in S3 segment of the renal proximal tubule is an “unknown-partner” of Slc3a1 (rBAT) (2014)
  • Author(s): Nagamori S
  • Organizer: Gordon Research Conference Membrane Transport Proteins
  • Place of Presentation: West Dover, VT, United States
  • Year and Date: 2014-07-13 – 2014-07-18
• [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: Marunouchi, Tokyo
• [Presentation] アミノ酸輸送体LAT1によって取り込まれたロイシンに対する細胞応答のリン酸プロテオミクスによる解析 (2013)
  • Author(s): 永森收志、Pattama Wiriyasermkul、世良田聡、仲哲治、金井好克
  • Organizer: 日本アミノ酸学会第７回学術大会
  • Place of Presentation: 熊本
• [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 (2013)
  • 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、愛知
  • Invited
• [Presentation] Functional coupling between a Na+-dependent anion transporter SMCT2 and a urate-anion exchanger URAT1 through a scaffold protein PDZK1. (2012)
  • Author(s): Shushi Nagamori, Yasuhiro Umemura, Pattama Wiriyasermkul, Saya Nakagomi, Yumiko Nishinaka, Kazuaki Takafuji, Ryuichi Ohgaki, Yoshikatsu Kanai.
  • Organizer: Gordon Research Conferences, Membrane Transport Proteins.
  • Place of Presentation: Les Diablerets, Switzerland
• [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 シンポジウム「分子標的診断・治療の進歩と今後」
  • Place of Presentation: 所沢、埼玉
  • Invited
• [Presentation] 日本人型シスチン尿症を発症させるアミノ酸トランスポーター変異体の機能解析
  • Author(s): 永森 收志、河本 泰治、Pattama Wiriyasermkul、金井 好克
  • Organizer: 生理学研究所研究会「上皮膜輸送の多層的コントロールによる生体の恒常性維持機構」
  • Place of Presentation: 岡崎、愛知
  • Invited
• [Presentation] Metabolomics and proteomics analyses of knockout mice reveal real physiological substrates of an organic anion transporter.
  • Author(s): Shushi Nagamori, Xi He, Taku Hirata, Pattama Wiriyasermkul, Saya Nakagomi, Takamasa Ishikawa, Tomoyoshi Soga, Yoshikatsu Kanai
  • Organizer: 第86回日本生化学会大会、International Session
  • Place of Presentation: 横浜、神奈川
  • 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: お茶の水、東京
  • 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, Yasuhiro Umemura, Pattama Wiriyasermkul, Yumiko Nishinaka, Noriyoshi Isozumi, Yoshikatsu Kanai
  • Organizer: The 58th Annual Meeting of the Biophysical Society
  • Place of Presentation: San Francisco､USA
• [Presentation] Evaluation of amino acid transporter LAT1 as a molecular target of anti-tumor therapy by means of the combination of comprehensive proteomics and transport assay網羅的プロテオミクスと輸送解析によるアミノ酸トランスポーター LAT1の抗腫瘍薬分子標的としての意義の検討
  • Author(s): 永森 收志、Pattama Wiriyasermkul、五十棲 規嘉、Pornparn Kongpracha、大垣 隆一、金井 好克
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
• [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、金井好克
  • Organizer: 2014年度日本農芸化学会 シンポジウム「トランスポーターを通して見る生命現象」
  • Place of Presentation: 生田、東京
  • Invited
• [Presentation] 日本人型シスチン尿症を発症させるアミノ酸トランスポーター変異体の機能解析
  • Author(s): 河本泰治, 永森收志, Pattama Wiriyasermkul,金井好克
  • Organizer: 日本生化学会近畿部会
  • Place of Presentation: 宇治市
• [Presentation] 腎尿細管に残された第二のシスチントランスポーターの分子同定
  • Author(s): 大垣 隆一, 奥山 裕久, Pattama Wiriyasermkul, 中込 咲綾, 西中 由美子, 高藤 和輝, 永森 收志, 金井 好克
  • Organizer: 第3回分子腎臓フォーラム
  • Place of Presentation: 東京
• [Presentation] 腎近位尿細管の第二のシスチントランスポーターの分子同定と機能解析
  • Author(s): 永森收志、奥山 裕久、Pattama Wiriyasermkul、中込 咲綾、西中 由美子、高藤 和輝、大垣 隆一、金井 好克
  • Organizer: 生理研研究会『粘膜防御における上皮膜輸送の役割とその破綻による疾病発症メカニズム』
  • Place of Presentation: 岡崎
• [Presentation] 質量分析計と再構成プロテオリポソームを用いた新規トランスポーター複合体の解析－腎尿細管に残された第二のシスチントランスポーターの分子同定
  • Author(s): 永森收志、奥山 裕久、Pattama Wiriyasermkul、中込 咲綾、西中 由美子、高藤 和輝、大垣 隆一、金井 好克
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡市