Study on_the protein-protein interaction regulating the function of amino acid transporters

• Project/Area Number: 17590226
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kyorin University
• Principal Investigator: KANAI Yoshikatsu Kyorin University, School of Medicine, Professor (60204533)
• Co-Investigator(Kenkyū-buntansha): ANZAI Naohiko Kyorin University, School of Medicine, Instructor (70276054) ; HIRATA Taku Kyorin University, School of Medicine, Instructor (60372918) ; UENO Takeshi Kyorin University, School of Medicine, Instructor (20406979) ; CHAIROUNGDUA A 杏林大学, 医学部, 助手 ; KIMIURA Toru Kyorin University, School of Medicine, Instructor (60383668) ; HOSOYAMADA Makoto Kyorin University, School of Medicine, Instructor (00291659)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Pharmacology / transporter / membrane protein / Protein-protein interaction / amino acid / membrane targeting / Functional regulation / scaffold protein

Research Abstract

Heterodimeric amino acid transporters are formed by disulfide bonding of a twelve-membrane spanning protein (catalytic subunit) and a single membrane spanning protein (regulatory subunit). We have performed BLAST searches of human and mouse genome data bases using amino acid sequences of LAT1, BAT1 and CAT1 as queries. We have found 5 new genes, SLC7-N1-5, as new members of SLC7 family. By searching EST (expressed sequence tag) data bases, we have concluded that two of them (SLC7 N4 and SLC7 N5) are pseudogenes, because they never appear in EST data bases. SLC7 -N1 possesses 12 transmembrane domains and is supposed to be a catalytic subunit of heterodimeric amino acid transporters. We have named it AGT 1. AGT 1 protein is found on the basolateral membrane of proximal and distal tubules of mouse kidney. Because AGT 1 is supposed to be linked with unknown regulatory subunit, we have generated fusion proteins in which AGT 1 is connected with known regulatory subunits 4F2hc or rBAT and expressed them in Xenopus oocytes. The fusion proteins appear on the plasma membrane and exhibit the transport of acidic amino acids. SLC7 N2 possesses 14 transmembrane domains and exhibits particularly high affinity to arginine, thus we named it CATS (cationic amino acid transporter 5). CAT5 is expressed in the syncytio-trophoblast of mouse placenta and supposed to mediate transport of amino acids through the placental bather as well as to supply placental cells with arginine as a precursor of NO synthesis. SLC7 N3 also possesses 14 transmembrane domains and transports small neutral amino acids as well as small basic amino acids, thus we have named it y^+Asc-1. In this study, the function of all the members of heterodimeric amino acid transporter family has been revealed. The results of this study would provide essential information to establish the basis for the genome-wide analyses of diseases or pathological conditions and facilitate drug design targeting the transporters of interest.

Research Products

• [Journal Article] Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones.Am J Physiol Renal Physiol.292:F361-F372,2007 (2007)
  • Author(s): Ljubojevic M, Balen D, Breljak D, Kusan M, Anzai A N, Bahn A, Burckhardt G, Sabolic I.
  • Journal Title: Am JPhysiol Renal Physiol 292
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] New Insights into Renal Transport of Urate (2007)
  • Author(s): Anzai N, Kanai Y, Endou H.
  • Journal Title: Curr Opin Rheumatol 19 Pages: 151-157
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract (2007)
  • Author(s): Nakamshi K Ogata S, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Aida S, Kasamatsu H, Kawai T.
  • Journal Title: Virchows Arch (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract (2007)
  • Author(s): Nakanishi, K, Ogata, S, Matsuo, H, Kanai, Y, Endou, H, Hiroi, S, Tominaga, S, Aida, S, Kasamatsu, H, Kawai, T
  • Journal Title: Virchows Arch (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] New Insights into Renal Transport of Urate. (2007)
  • Author(s): Anzai N, et al.
  • Journal Title: Curr Opin Rheumatol. 19 Pages: 151-157
• [Journal Article] Role of Mouse Organic Anion Transporter 3 (mOat3) as a Basolateral Prostaglandin E(2) Transport Pathway. (2007)
  • Author(s): Nilwarangkoon S, et al.
  • Journal Title: J Pharmacol Sci. 103 Pages: 48-55
• [Journal Article] Dual-color imaging of nuclear-cytoplasmic dynamics, viability, and proliferation of cancer cells in the portal vein area (2006)
  • Author(s): Tsuji K, Yamauchi K, Yang M, Jiang P, Bouvet M, Endo H, Kanai Y, Yamashita K, Moossa AR, Hoffman RM
  • Journal Title: Cancer Res 66 Pages: 303-306
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 有機カチオン/アニオントランスポーター、日本臨牀2006年増刊号「分子腎臓病学-分子生物学的アブローチと分子病態生理学-」169-175,2006. (2006)
  • Author(s): 金井 好克
  • Journal Title: 日本臨牀2006年増刊号「分子腎臓病学-分子生物学的アプローチと分子病態生理学-」 Pages: 169-175
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] アミノ酸輸送体と疾患 (2006)
  • Author(s): 金井 好克
  • Journal Title: 医学のあゆみ 216 Pages: 692-698
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] アミノ酸トランスポーター (2006)
  • Author(s): 金井 好克
  • Journal Title: 細胞工学 25 Pages: 280-286
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of rat renal cortical OAT1 and OAT3 in response to acute iliary obstruction (2006)
  • Author(s): Brandoni A, Villar SR, Picena JC, Anzai N, Endou H, Tones AM
  • Journal Title: Hepatology 43 Pages: 1092-1100
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of steroid hormone biosynthesis enzymes and organic anion transporters by forskolin and DHEAS treatment in adrenocortical cells (2006)
  • Author(s): Asif AR, Ljubojevic M, Sabolic I, Shnitsar V, Metten M, Anzai N, Mueller GA Burckhardt G, Hagos Y.
  • Journal Title: Am JPhysiol Endocrinol Metab 291
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of amino acid transporter LAT1 and 4F2hc in the healing process after the implantation of a tooth ash and plaster of Paris mixture (2006)
  • Author(s): Kim SG, Ahn YC, Yoon JH, Kim HK, Park SS, Ahn SG, Endou H, Kanai Y, Park JC, Kim do K
  • Journal Title: In Vivo 20 Pages: 591-597
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The RNA inteference of amino acid fransporter LAT1 inhibits the growth of KB human oral cancer cells (2006)
  • Author(s): Kim CH, Park KJ, Park JR, Kanal Y, Endou H, Park JC, Kim do K
  • Journal Title: Anticancer Res 26 Pages: 2943-2948
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Localization of Ang-1,-2,Tie-2,and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis (2006)
  • Author(s): Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, Hano H, Endou H, Kanal Y
  • Journal Title: Lab Invest 86 Pages: 1172-1184
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung (2006)
  • Author(s): Nakanishi, K, Matsuo, H, Kanai, Y, Endou, H, Hiroi, S, Tominaga, S, Mukai, M, Ikeda, E, Ozeki, Y, Aida, S, Kawai, T
  • Journal Title: Virchows Arch 448 Pages: 142-150
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prenatal 3, 3', 4, 4', 5-pentachlorobiphenyl exposure modulates induction of rat hepatic CYP 1A1, 1B1, and AhR by 7, 12-d methylbenz[a]anthracene (2006)
  • Author(s): Wakui, S, Yokoo, K, Takahashi, H, Muto, T, Suzuki, Y, Kanai, Y, Hano, H, Furusato, M, Endou, H
  • Journal Title: Toxicol Appl Pharmacol 210 Pages: 200-211
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter (2006)
  • Author(s): Shigeta, Y, Kanai, Y, Chairoungdua, A, Ahmed, N, Sakamoto, S, Matsuo, H, Kim, DK, Fujimura, M, Anzai, N, Mizoguchi, K, Ueda, T, Akakura, K, Ichikawa, T, Ito, H, Endou, H
  • Journal Title: Kidney Int 69 Pages: 1198-1206
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity (2006)
  • Author(s): Noshiro, R, Anzai, N, Sakata, T, Miyazaki, H, Terada, T, Shin, HJ, He, X, Miura, D, Inui, K, Kanai, Y, Endou, H
  • Journal Title: Kidney Int 70 Pages: 275-282
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction (2006)
  • Author(s): Brandoni, A, Villar, SR, Picena, JC, Anzai, N, Endou, H, Torres, AM
  • Journal Title: Hepatology 43 Pages: 1092-1100
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human vascular smooth muscle cells express a urate transporter (2006)
  • Author(s): Price, KL, Sautin, YY, Long, DA, Zhang, L, Miyazaki, H, Mu, W, Endou, H, Johnson, RJ
  • Journal Title: J Am Soc Nephrol 17 Pages: 1791-1795
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Organic anion transporter family : current knowledge (2006)
  • Author(s): Anzai, N, Kanai, Y, Endou, H
  • Journal Title: J Am Soc Nephrol 17 Pages: 1791-1795
  • NAID: 10018238661
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Treatment effects and predictors of a 24-week course of interferon alpha-2b plus ribavirin combination therapy for patients with chronic hepatitis C (2006)
  • Author(s): Tomimatsu, M, Aizawa, Y, Chuganji, Y, Ishizuka, H, Fujita, Y, Aizawa, R, Abe, H, Matsuda, T, Itou, Y, Nakanishi, H, Ushiyama, H, Higuchi, T, Fujimoto, T, Endou, H, Iga, D, Ohta, K, Kuroda, H
  • Journal Title: J Gastroenterol Hepatol 21 Pages: 1177-1183
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Renal elimination of p-aminohippurate(PAH)in respose to three days of biliary obstruction in the rat. The role of OAT1 and OAT3 (2006)
  • Author(s): Brandoni, A, Anzai, N, Kanai, Y, Endou, H, Torres, AM
  • Journal Title: Biochim Biophys Acta 1762 Pages: 673-682
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors (2006)
  • Author(s): Nawashiro, H, Otani, N, Shinomiya, N, Fukui, S, Ooigawa, H, Shima, K, Matsuo, H, Kanai, Y, Endou, H
  • Journal Title: Mt. J Cancer 119 Pages: 484-492
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential expression and functional characterization of system L amino acid transporters in human normal osteoblast cells and osteogenic sarcoma cells (2006)
  • Author(s): Kim, SG, Kim, HH, Kim, HK, Kim, CH, Chun, HS, Kanai, Y, Endou, H, Kim, do, K
  • Journal Title: Anticancer Res 26 Pages: 1989-1996
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter. (2006)
  • Author(s): Shigeta Y, et al.
  • Journal Title: Kidney Int. 69 Pages: 1198-1206
• [Journal Article] The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. (2006)
  • Author(s): Noshiro R, et al.
  • Journal Title: Kidney Int. 70 Pages: 275-282
• [Journal Article] Organic anion transporter family : current knowledge. (2006)
  • Author(s): Anzai N, et al.
  • Journal Title: Pharmacol Sci. 100 Pages: 411-426
  • NAID: 10018238661
• [Journal Article] Renal elimination of p-aminohippurate (PAH) in respose to three days of biliary obstruction in the rat. The role of OAT1 and OAT3. (2006)
  • Author(s): Brandoni A, et al.
  • Journal Title: Biochim Biophys Acta. 1762 Pages: 673-682
• [Journal Article] L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. (2006)
  • Author(s): Nawashiro H, et al.
  • Journal Title: In J. Cancer : 119 Pages: 484-492
• [Journal Article] Differential expression and functional characterization of system Lamino acid transporters in human normal osteoblast cells and osteogenic sarcoma cells. (2006)
  • Author(s): Kim SG, et al.
  • Journal Title: Anticancer Res. Pages: 1989-1996
• [Journal Article] Expression of amino acid transporter LAT1 and 4F2hc in the healing process after the implantation of a tooth ash and plaster of Paris mixture. (2006)
  • Author(s): Kim SG, et al.
  • Journal Title: In Vivo. 20 Pages: 591-597
• [Journal Article] The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. (2006)
  • Author(s): Kim CH, et al.
  • Journal Title: Anticancer Res. : 26 Pages: 2943-2948
• [Journal Article] Localization of Mg-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. (2006)
  • Author(s): Wakui S, et al.
  • Journal Title: Lab Invest. 86 Pages: 1172-1184
• [Journal Article] Dual-color imaging of nuclear-cytoplasmic dynamics, viability, and proliferation of cancer cells in the portal vein area. (2006)
  • Author(s): Tsuji K
  • Journal Title: Cancer Res 66 Pages: 303-306
• [Journal Article] LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. (2006)
  • Author(s): Nakanishi K
  • Journal Title: Virchows Arch 448 Pages: 142-150
• [Journal Article] Prenatal 3,3',4,4',5-pentachlorobiphenyl exposure modulates induction of rat hepatic CYP 1A1, 1B1, and AhR by 7,12-dimethylbenz[a]anthracene. (2006)
  • Author(s): Wakui S
  • Journal Title: Toxicol Appl Pharmacol 210 Pages: 200-211
• [Journal Article] A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter. (2006)
  • Author(s): Shigeta, Y
  • Journal Title: Kidney Int. (in press)
• [Journal Article] The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. (2006)
  • Author(s): Noshiro R
  • Journal Title: Kidney Int. (in press)
• [Journal Article] アミノ酸トランスポーター (2006)
  • Author(s): 金井好克
  • Journal Title: Medical Tribune 39(2) Pages: 34-34
• [Journal Article] 有機カチオン/アニオントランスポーター (2006)
  • Author(s): 金井好克
  • Journal Title: 日本臨牀2006年増刊号「分子腎臓病学-分子生物学的アプローチと分子病態生理学-」 Pages: 169-175
• [Journal Article] アミノ酸輸送体と疾患 (2006)
  • Author(s): 金井好克
  • Journal Title: 医学のあゆみ 216 Pages: 692-698
• [Journal Article] アミノ酸トランスポーター (2006)
  • Author(s): 金井好克
  • Journal Title: 細胞工学 25 Pages: 280-286
• [Journal Article] Establishment of a Mouse Macula Densa Cell Line with an nNOS Promoter Driving EGFP Expression (2005)
  • Author(s): Yasuoka Y, Kawada H, Suzuki Y, Sato M, Endou H, Obinata M, Kawahara K
  • Journal Title: Jpn J Physiol 55 Pages: 365-372
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] unctional expression of the rat organic anion transporter 1 (rOAT1) in Saccharomyces cerevisiae (2005)
  • Author(s): Sawamiphak S, Sophasan S, Endou H. Boonchird C
  • Journal Title: Biochim Biophys Acta 1720 Pages: 44-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureera obsfructton (2005)
  • Author(s): Villar SR, Brandon A, Anzai N, Endou H, Torres AM.
  • Journal Title: Kidney Int 68 Pages: 2704-2713
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Renal urate handling:clinical relevance of recent advances (2005)
  • Author(s): Anzai N, Enomoto A, Endou H
  • Journal Title: Curr Rheumatol Rep 7 Pages: 227-234
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered renal elimination of organic anions in rats with chronic renal failure (2005)
  • Author(s): Monica Torres A, Mac Laughlin M, Muller A, Brandoni A, Anzai N, Endou H
  • Journal Title: Biochim Biophys Acta 1740 Pages: 29-37
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 腎尿細管のトランスポーター:疾患から機能へのアプローチ (2005)
  • Author(s): 金井 好克
  • Journal Title: 日本尿路結石症学会誌 4(2) Pages: 1-17
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ことばのカルテ:アミノ酸トランスポーター (2005)
  • Author(s): 金井 好克
  • Journal Title: Medical Tribune 39(2) Pages: 34-34
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reabsorption of neutral amino acids mediated by amino acid transporter LAT2 and TAT1 in the basolateral membrane of proximal tubule. (2005)
  • Author(s): Park SY
  • Journal Title: Arch Parm Res 28(4) Pages: 421-432
• [Journal Article] Amino acid transport system L is differently expressed human normal oral keratinocytes and human oral cancer cells (2005)
  • Author(s): Yoon JH
  • Journal Title: Cancer Lett. 222 Pages: 237-245
• [Journal Article] Integrated physiology and proximal tubular organic anion transport. (2005)
  • Author(s): Anzai N
  • Journal Title: Curr Opin Nephrol Hypertens 14 Pages: 472-479
• [Journal Article] Functional Characterization of rat organic anion transporter 5 (Slc 22a19) at the apical membrane of renal proximal tubules. (2005)
  • Author(s): Anzai N
  • Journal Title: J Pharmacol Exp Ther 315 Pages: 534-544
• [Journal Article] Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins. (2005)
  • Author(s): Miyazaki H
  • Journal Title: J. Am. Soc Nephol 16 Pages: 3498-3506
• [Journal Article] CYP1 and AhR expression in 7,12-dimethylbenz[a]anthracene-induced mammary carcinoma of rats prenatally exposed to 3,3',4,4',5-pentachlorobiphenyl. (2005)
  • Author(s): Wakui S
  • Journal Title: Toxicology 211 Pages: 231-241
• [Journal Article] Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction. (2005)
  • Author(s): Villar SR
  • Journal Title: Kidney Int. 68 Pages: 2704-2713
• [Journal Article] Renal urate handling : clinical relevance of recent advances. (2005)
  • Author(s): Anzai N
  • Journal Title: Curr Rheumatol Rep. 7 Pages: 227-234
• [Journal Article] Altered renal elimination of organic anions in rats with chronic renal failure. (2005)
  • Author(s): Monica Torres A
  • Journal Title: Biochim Biophys Acta 1740 Pages: 29-37
• [Journal Article] Glucose transpoter2 (GLUT2) (2005)
  • Author(s): 金井好克
  • Journal Title: 腎と透析 59 Pages: 582-584
• [Journal Article] Urate transporter1 (URAT1) (2005)
  • Author(s): 金井好克
  • Journal Title: 腎と透析 59 Pages: 586-588
• [Journal Article] 腎尿細管のトランスポーター:疾患から機能へのアプローチ (2005)
  • Author(s): 金井好克
  • Journal Title: 日本尿路結石症学会誌 4(2) Pages: 1-17
• [Journal Article] Fluorine-18-α-methyltyrosine positron emission tomography for diagnosis and staging of lung cancer:A clinicopathological study
  • Author(s): Kaua, K, Oriuchi, N, Otam, Y, Shimizu, K, Tanaka, S, Imai, H, Yanagitani, N, Sunaga, N, Hisada, T, Ishizuka, T, Dobashi, K, Kanai, Y, Endou, H, Nakajima, T, Endo, K, Mori, M
  • Journal Title: Clin.Cancer Res (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells
  • Author(s): Kobayashi, K, Ohnishi, A, Promsuk, J, Kanai, Y, Endou, H, Shiokawa, Y, Nagane, M
  • Journal Title: Neurosurgery (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fluorine-18- α -methyltyrosine positron emission tomography for diagnosis and staging of lung cancer : A clinicopathological study
  • Author(s): Kaira, K, Oriuchi, N, Otani, Y, Shimizu, K, Tanaka, S, Imai, H, Yanagitani, N, Sunaga, N, Hisada, T, Ishizuka, T, Dobashi, K, Kanai, Y, Endou, H, Nakajima, T, Endo, K, Mori, M
  • Journal Title: Clin. Cancer Res (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells.
  • Author(s): Kobayashi K, et al.
  • Journal Title: Neurosurgery in press
• [Book] Annual Review 2007 腎臓、中外医学社、2007,p.42-49 (2007)
  • Author(s): 平田 拓
  • Total Pages: 8
  • Publisher: 腎におけるプロスタグランジンシグナリングの新展開
• [Book] AnnualReview2007腎臓 (2006)
  • Author(s): 平田 拓、金井 好克
  • Total Pages: 8
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より