Biological Systems Control Team





私たちのチームは、高精度のタンパク質ネットワーク大規模解析を目指し研究を進めています。

タンパク質は生物にとって不可欠な分子です。
生体内には多くのタンパク質が存在していますが、それぞれのタンパク質が単独で機能することはほとんどありません。 他のタンパク質と相互作用し、ネットワークを形成してその機能を発揮しているのです。 タンパク質ネットワークを明らかにすることは、生物の発生・分化から組織構築、そして死に至るすべての生命現象を理解する上で重要です。

また、タンパク質ネットワーク情報は、疾患の発症メカニズムの解明にも有用です。 生命現象を担っているタンパク質ネットワークの破綻が疾患につながることが明らかにされています。 疾患関連タンパク質のネットワークを解明することにより、疾患の発症メカニズムをタンパク質レベルで把握し、その創薬ターゲットの同定が可能になります。

このように、タンパク質ネットワーク情報は、基礎研究から創薬にいたる幅広い分野に有用な情報なのです。

私たちは、意味のあるタンパク質ネットワーク情報を高精度で大規模に取得するために、以下の３つの解析システムを独自に開発しました。

　・質量分析のための自動サンプル調製システム
　・超高感度ダイレクトナノLCタンデム質量分析システム
　・高速・高精度タンパク質検索・同定システム

これらのシステムを駆使し、これまでに様々な新規生物システムの発見という成果を得ています。
さらなる貢献を目指し、解析システムのさらなる高感度化・高精度化を進めながら、タンパク質ネットワークの解析を精力的に進めます。








1800種のヒトcDNA（精製タグ付き）を細胞に導入し、導入cDNA由来タンパク質画分を抽出。
それらのタンデムマス解析により600種類のタンパク質複合体の同定。
その中から疾病関連タンパク質を含む100種の新規相互作用の発見。

2010

SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kgamma Activity through Deacetylation of Specific Lysine Residues in Mammals. PLoS. One. 5, e11755 S. Akieda-Asai, N. Zaima, K. Ikegami, T. Kahyo, I. Yao, T. Hatanaka, S. Iemura, R. Sugiyama, T. Yokozeki, Y. Eishi, M. Koike, K. Ikeda, T. Chiba, H. Yamaza, I. Shimokawa, S. Y. Song, A. Matsuno, A. Mizutani, M. Sawabe, M. V. Chao, M. Tanaka, Y. Kanaho, T. Natsume, H. Sugimura, Y. Date, M. W. McBurney, L. Guarente, and M. Setou.

Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J. Biol. Chem. 285, 20109-20116 T. Kaizuka, T. Hara, N. Oshiro, U. Kikkawa, K. Yonezawa, K. Takehana, S. Iemura, T. Natsume, and N. Mizushima.

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell. Biol. 12, 213-223. M. Komatsu, H. Kurokawa, S. Waguri, K. Taguchi, A. Kobayashi, Y. Ichimura, Y. S. Sou, I. Ueno, A. Sakamoto, K. I. Tong, M. Kim, Y. Nishito, S. Iemura, T. Natsume, T. Ueno, E. Kominami, H. Motohashi, K. Tanaka, and M. Yamamoto.

Mys protein regulates protein kinase A activity by interacting with regulatory type Ialpha subunit during vertebrate development. J. Biol. Chem. 285, 5106-5116. T. Kotani, S. Iemura, T. Natsume, K. Kawakami, and M. Yamashita.

A novel human dynactin-associated protein, dynAP, promotes activation of Akt, and ergosterol-related compounds induce dynAP-dependent apoptosis of human cancer cells. Mol. Cancer. Ther. 9, 2934-2942. T. Kunoh, T. Noda, K. Koseki, M. Sekigawa, M. Takagi, K. Shin-ya, N. Goshima, S. Iemura, T. Natsume, S. Wada, Y. Mukai, S. Ohta, R. Sasaki, and T. Mizukami.

Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 466, 941-946. S. Nakada, I. Tai, S. Panier, A. Al-Hakim, S. Iemura, Y. C. Juang, L. O'Donnell, A. Kumakubo, M. Munro, F. Sicheri, A. C. Gingras, T. Natsume, T. Suda, and D. Durocher.

The PX-RICS-14-3-3zeta/theta complex couples N-cadherin-beta-catenin with dynein-dynactin to mediate its export from the endoplasmic reticulum. J. Biol. Chem. 285, 16145-16154. T. Nakamura, T. Hayashi, Y. Mimori-Kiyosue, F. Sakaue, K. Matsuura, S. Iemura, T. Natsume, and T. Akiyama.

Nemo-like kinase, an essential effector of anterior formation, functions downstream of p38 mitogen-activated protein kinase. Mol. Cell. Biol. 30, 675-683. E. Ohnishi, T. Goto, A. Sato, M. S. Kim, S. Iemura, T. Ishitani, T. Natsume, J. Ohnishi, and H. Shibuya.

Novel thioredoxin-related transmembrane protein TMX4 has reductase activity. J. Biol. Chem. 285, 7135-7142. Y. Sugiura, K. Araki, S. Iemura, T. Natsume, J. Hoseki, and K. Nagata.

Comparative analysis of human SRC-family kinase substrate specificity in vitro. J. Proteome. Res. 9, 5982-5993. H. Takeda, Y. Kawamura, A. Miura, M. Mori, A. Wakamatsu, J. Yamamoto, T. Isogai, M. Matsumoto, K. I. Nakayama, T. Natsume, N. Nomura, and N. Goshima.

A novel type of E3 ligase for the Ufm1 conjugation system. J. Biol. Chem. 285, 5417-5427. K. Tatsumi, Y. S. Sou, N. Tada, E. Nakamura, S. Iemura, T. Natsume, S. H. Kang, C. H. Chung, M. Kasahara, E. Kominami, M. Yamamoto, K. Tanaka, and M. Komatsu.

2009

A novel Grb2 associating protein (Gasp) is critical for positiveselection of thymocytes. PNAS. MS#2009-08593. Michael, P., Oda, H., Hayakawa, K., Sato, Y., Eshima, K., Kirikae, T., Iemura, S., Shirai, M., Abe, T., Natsume, T., Sasazuki, T., Suzuki, H.

Novel In Vitro Protein Fragment Complementation Assay Applicable to High-Throughput Screening in a 1536-Well Format. J Biomol Screen. 14(8), 970-979. Hashimoto, J., T. Watanabe, T. Seki, S. Karasawa, M. Izumikawa, T. Seki, S.I. Iemura, T. Natsume, N. Nomura, N. Goshima, A. Miyawaki, M. Takagi, K. Shin-Ya.

Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Molecular biology of the cell. 20(7), 1981-1991. Hosokawa, N., T. Hara, T. Kaizuka, C. Kishi, A. Takamura, Y. Miura, S. Iemura, T. Natsume, K. Takehana, N. Yamada, J.L. Guan, N. Oshiro, N. Mizushima.

Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy. 18, 5(7). Hosokawa, N., T. Sasaki, S.I. Iemura, T. Natsume, T. Hara, N. Mizushima.

Promotion of neurite extension by protrudin requires its interaction. Journal of Biological Chemistry. Saita, S., Shirane, M., Natsume, T., Iemura, S., Nakayama, K.

Quantitative analysis of first-pass contrast-enhanced myocardial perfusion MRI using a Patlak plot method and blood saturation correction. Magn Reson Med. 62(2), 373-383. Ichihara, T., M. Ishida, K. Kitagawa, Y. Ichikawa, T. Natsume, N. Yamaki, H. Maeda, K. Takeda, H. Sakuma.

Assembly pathway of the Mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell. 137(5), 914-925. Kaneko, T., J. Hamazaki, S. Iemura, K. Sasaki, K. Furuyama, T. Natsume, K. Tanaka, S. Murata.

Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation. The Journal of biological chemistry. 284(16), 10694-10705. Kiefer, H., A. Mizutani, S. Iemura, T. Natsume, H. Ando, Y. Kuroda, K. Mikoshiba.

CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis. Nature cell biology. 11(2), 172-182. Nishiyama, M., K. Oshikawa, Y. Tsukada, T. Nakagawa, S. Iemura, T. Natsume, Y. Fan, A. Kikuchi, A.I. Skoultchi, K.I. Nakayama.

Asef2 and Neurabin2 cooperatively regulate actin cytoskeletal organization and are involved in HGF-induced cell migration. Oncogene. 28(10), 1357-1365. Sagara, M., Y. Kawasaki, S.I. Iemura, T. Natsume, Y. Takai, T. Akiyama.

Ankyrin repeat domain 28 (ANKRD28), a novel binding partner of DOCK180, promotes cell migration by regulating focal adhesion formation. Experimental cell research. 315(5), 863-876. Tachibana, M., E. Kiyokawa, S. Hara, S. Iemura, T. Natsume, T. Manabe, M. Matsuda.

Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1. Proceedings of the National Academy of Sciences of the United States of America. 106(30), 12301-12305. Takeda, K., Y. Komuro, T. Hayakawa, H. Oguchi, Y. Ishida, S. Murakami, T. Noguchi, H. Kinoshita, Y. Sekine, S. Iemura, T. Natsume, H. Ichijo.

The transmembrane nucleoporin NDC1 is required for targeting of ALADIN to nuclear pore complexes. Biochemical and biophysical research communications. 6 ;389(1),100-4. Yamazumi, Y., A. Kamiya, A. Nishida, A. Nishihara, S.I. Iemura, T. Natsume, T. Akiyama.

2008

Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7. The Journal of biological chemistry. 283(9), 5518-5524. Hamuro, J., O. Higuchi, K. Okada, M. Ueno, S. Iemura, T. Natsume, H. Spearman, D. Beeson, Y. Yamanashi.

The DHR1 domain of DOCK180 binds to SNX5 and regulates cation-independent mannose 6-phosphate receptor transport. Molecular biology of the cell. 19(9), 3823-3835. Hara, S., E. Kiyokawa, S. Iemura, T. Natsume, T. Wassmer, P.J. Cullen, H. Hiai, M. Matsuda.

FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. The Journal of cell biology. 181(3), 497-510. Hara, T., A. Takamura, C. Kishi, S. Iemura, T. Natsume, J.L. Guan, N. Mizushima.

A parallel affinity purification method for selective isolation of polyubiquitinated proteins. Proteomics. 8(15), 3004-3007. Ota, K., K. Kito, S. Iemura, T. Natsume, T. Ito.

Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron. 57(1), 94-107. Saneyoshi, T., G. Wayman, D. Fortin, M. Davare, N. Hoshi, N. Nozaki, T. Natsume, T.R. Soderling.

CAATT/enhancer-binding proteins alpha and delta interact with NKX2-1 to synergistically activate mouse secretoglobin 3A2 gene expression. The Journal of biological chemistry. 283(37), 25617-25627. Tomita, T., T. Kido, R. Kurotani, S. Iemura, E. Sterneck, T. Natsume, C. Vinson, S. Kimura.

Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7. The Journal of biological chemistry. 283(9), 5518-5524. Hamuro, J., O. Higuchi, K. Okada, M. Ueno, S. Iemura, T. Natsume, H. Spearman, D. Beeson, Y. Yamanashi.

2007

Wnt signalling regulates paxillin ubiquitination essential for mesodermal cell motility. Nature cell biology. 9(7), 813-821. Iioka, H., S. Iemura, T. Natsume, N. Kinoshita.

Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 131(6), 1149-1163. Komatsu, M., S. Waguri, M. Koike, Y.S. Sou, T. Ueno, T. Hara, N. Mizushima, J. Iwata, J. Ezaki, S. Murata, J. Hamazaki, Y. Nishito, S. Iemura, T. Natsume, T. Yanagawa, J. Uwayama, E. Warabi, H. Yoshida, T. Ishii, A. Kobayashi, M. Yamamoto, Z. Yue, Y. Uchiyama, E. Kominami, K. Tanaka.

XRab40 and XCullin5 form a ubiquitin ligase complex essential for the noncanonical Wnt pathway. The EMBO journal. 26(15), 3592-3606. Lee, R.H., H. Iioka, M. Ohashi, S. Iemura, T. Natsume, N. Kinoshita.

Anchoring of the 26S proteasome to the organellar membrane by FKBP38. Genes Cells. 12(6), 709-719. Nakagawa, T., M. Shirane, S. Iemura, T. Natsume, K.I. Nakayama.

Nucleocytoplasmic shuttling of the zinc finger protein EZI Is mediated by importin-7-dependent nuclear import and CRM1-independent export mechanisms. The Journal of biological chemistry. 282(44), 32327-32337. Saijou, E., T. Itoh, K.W. Kim, S. Iemura, T. Natsume, A. Miyajima.

Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development. Molecular and cellular biology. 27(21), 7623-7630. Satoh, K., J. Ohnishi, A. Sato, M. Takeyama, S. Iemura, T. Natsume, H. Shibuya.

New aureothin derivative, alloaureothin, from Streptomyces sp. MM23. The Journal of antibiotics. 60(5), 321-324. Ueda, J.Y., J. Hashimoto, A. Nagai, T. Nakashima, H. Komaki, K. Anzai, S. Harayama, T. Doi, T. Takahashi, K. Nagasawa, T. Natsume, M. Takagi, K. Shin-ya.

A novel nuclear export inhibitor JBIR-02, a new piericidin discovered from Streptomyces sp. ML55. The Journal of antibiotics. 60(7), 459-462. Ueda, J.Y., T. Togashi, S. Matukura, A. Nagai, T. Nakashima, H. Komaki, K. Anzai, S. Harayama, T. Doi, T. Takahashi, T. Natsume, Y. Kisu, N. Goshima, N. Nomura, M. Takagi, K. Shin-Ya.

2006

A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. The EMBO journal. 25(19), 4524-36. Hamazaki, J., Iemura, S., Natsume, T., Yashiroda, H., Tanaka, K., and Murata, S.

Cooperation of Multiple Chaperones Required for the Assembly of Mammalian 20S Proteasomes. Molecular cell. 24(6), 977-84. Hirano, Y., Hayashi, H., Iemura, S., Hendil, K.B., Niwa, S., Kishimoto, T., Kasahara, M., Natsume, T., Tanaka, K., and Murata, S.

XGAP, an ArfGAP, is required for polarized localization of PAR proteins and cell polarity in Xenopus gastrulation. Dev Cell. 11(1), 69-79. Hyodo-Miura, J., Yamamoto, T.S., Hyodo, A.C., Iemura, S., Kusakabe, M., Nishida, E., Natsume, T., and Ueno, N.

Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. The Journal of biological chemistry. 281(52), 39891-6. Kajino, T., Ren, H., Iemura, S., Natsume, T., Stefansson, B., Brautigan, D.L., Matsumoto, K., and Ninomiya-Tsuji, J.

Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature. 441(7089), 46-52. Epub 2006 Mar 2015. Kitajima, T.S., Sakuno, T., Ishiguro, K., Iemura, S., Natsume, T., Kawashima, S.A., and Watanabe, Y.

Comparative genomic analysis of transcription regulation elements involved in human map kinase g-protein coupling pathway. J Bioinform Comput Biol. 4(2), 469-82. Polouliakh, N., Natsume, T., Harada, H., Fujibuchi, W., and Horton, P.

Proteomic profiling of lipid droplet proteins in hepatoma cell lines expressing hepatitis C virus core protein. J Biochem (Tokyo). 139(5), 921-30. Sato, S., Fukasawa, M., Yamakawa, Y., Natsume, T., Suzuki, T., Shoji, I., Aizaki, H., Miyamura, T., and Nishijima, M.

Cdc37 interacts with the glycine-rich loop of Hsp90 client kinases. Mol Cell Biol. 26(9), 3378-89. Terasawa, K., Yoshimatsu, K., Iemura, S., Natsume, T., Tanaka, K., and Minami, Y.

NARF, an Nemo-like Kinase (NLK)-associated Ring Finger Protein Regulates the Ubiquitylation and Degradation of T Cell Factor/Lymphoid Enhancer Factor (TCF/LEF). J Biol Chem. 281(30), 20749-60. Yamada, M., Ohnishi, J., Ohkawara, B., Iemura, S., Satoh, K., Hyodo-Miura, J., Kawachi, K., Natsume, T., and Shibuya, H.

A novel ubiquitin-binding protein ZNF216 functioning in muscle atrophy. Embo J. 25(3), 554-64. Hishiya, A., Iemura, S., Natsume, T., Takayama, S., Ikeda, K., and Watanabe, K.

Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases. Genes Cells. 11(2), 143-51. Honma, M., Higuchi, O., Shirakata, M., Yasuda, T., Shibuya, H., Iemura, S., Natsume, T., and Yamanashi, Y.

2005

JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol. 7(3), 278-85. Yoshida, K., Yamaguchi, T., Natsume, T., Kufe, D., and Miki, Y.

Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44. Cell. 120(1), 85-98. Higo, T., Hattori, M., Nakamura, T., Natsume, T., Michikawa, T., and Mikoshiba, K.

2004

A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier. Embo J. 23(9), 1977-86. Komatsu, M., Chiba, T., Tatsumi, K., Iemura, S., Tanida, I., Okazaki, N., Ueno, T., Kominami, E., Natsume, T., and Tanaka, K.

Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell. 6(5), 661-72. Nakayama, K., Nagahama, H., Minamishima, Y.A., Miyake, S., Ishida, N., Hatakeyama, S., Kitagawa, M., Iemura, S., Natsume, T., and Nakayama, K.I.