Medical Proteomics Laboratory

シグナル伝達系は細胞の増殖・分化など複雑な生命現象を広く制御することが知られています。実際のシグナル伝達においてはタンパク質のリン酸化が主要な役割を果たしていることから、リン酸化タンパク質群の動態を包括的に把握することは制御機構の本質的な解明に必須であると考えられます。私たちのグループでは、最先端の高感度nanoLC-MS/MSシステムによるショットガンプロテオーム解析技術とアミノ酸安定同位体ラベルによる高精度相対定量技術を組み合わせ、ネットワーク構成因子に関するダイナミクスデータをハイスループットに取得するシステムを確立しました (Oyama et al., Mol Cell Proteomics, 2009)。本システムに基づくネットワーク解析により、文献情報に基づく既存のパスウェイ構造を包括的に検証・修正することが可能になります。今後医科学研究所内外の各種疾患解析をリードするグループとの共同研究により、疾患ごとのリン酸化ネットワークの特性の理解と創薬ターゲットの探索に向けた解析基盤の構築を進めていきたいと考えています。

ヒトゲノム配列の解読と並行し、転写産物の網羅的な配列解析も国際レベルで精力的に進められてきました。興味深いことに、代表的なヒト遺伝子に関する全長cDNAの配列解析から、約半数の遺伝子が5’末端の非翻訳領域に短いORFを有していることが示されました。翻訳開始システムとして従来提唱されているスキャニングメカニズムに従って、これらの小ORFが実際に細胞中で翻訳されているか否かを実験的に明らかにすることは、ヒトプロテオームの真の全体像を理解するために必要不可欠であると考えられます。私たちは低分子タンパク質に焦点を絞ったショットガンプロテオーム解析により、mRNAの5’-端非翻訳領域に由来する翻訳産物を世界で初めて直接同定することに成功しました(Oyama et al., Genome Res, 2004)。さらに二次元nanoLC-MS/MSシステムによる大規模な同定解析により、選択的な転写開始やスプライシングによる転写産物の構造調節、並びに翻訳開始部位の調節によって規定される多様なタンパク質コード領域の存在が示され、ヒトプロテオームの多様性に寄与する翻訳開始制御システムの新たな一端が明らかになりました (Oyama et al., Mol Cell Proteomics, 2007)。

Hino N^*, Oyama M^*, Sato A, Mukai T, Iraha F, Hayashi A, Kozuka-Hata H,　Yamamoto T, Yokoyama S, and Sakamoto K. (^* ; equal contribution)
Genetic incorporation of a photo-crosslinkable amino acid reveals novel protein complexes with GRB2 in mammalian cells.
J. Mol. Biol., in press.

Oyama M^*#, Nagashima T^*, Suzuki T, Kozuka-Hata H, Yumoto N, Shiraishi Y, Ikeda K, Kuroki Y, Gotoh N, Ishida T, Inoue S, Kitano H, and Okada-Hatakeyama M^#. (^* ; equal contribution) (^# ; corresponding authors)
Integrated quantitative analysis of the phosphoproteome and transcriptome in tamoxifen-resistant breast cancer.
J. Biol. Chem., in press.

Tasaki S, Nagasaki M, Kozuka-Hata H, Semba K, Gotoh N, Hattori S, Inoue J, Yamamoto T, Miyano S, Sugano S, and Oyama M^#. (^# ; corresponding author)
Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.
PLoS One, 5: e13926, 2010.

Arii J, Goto H, Suenaga T, Oyama M, Kozuka-Hata H, Imai T, Minowa A, Akashi H, Arase H, Kawaoka Y, and Kawaguchi Y.
Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus 1.
Nature, 467: 859-862, 2010.

Matsumura T, Oyama M, Kozuka-Hata H, Ishikawa K, Inoue T, Muta T, Semba K, and Inoue J.
Identification of BCAP-(L) as a negative regulator of the TLR signaling-induced production of IL-6 and IL-10 in macrophages by tyrosine phosphoproteomics.
Biochem. Biophys. Res. Commun., 400: 265-270, 2010.

Fujita T, Kozuka-Hata H, Uno Y, Nishikori K, Morioka M, Oyama M, and Kubo T.
Functional analysis of the honeybee (Apis mellifera L.) salivary system using proteomics.
Biochem. Biophys. Res. Commun., 397: 740-744, 2010.

Oyama M^#, Tasaki S, and Kozuka-Hata H. (^# ; corresponding author)
Tyrosine-Phosphoproteome Dynamics.
In Systems Biology for Signaling Networks（ed. Choi, S）, Springer, 447-454, 2010.

Tsujita K, Itoh T, Kondo A, Oyama M, Kozuka-Hata H, Irino Y, Hasegawa J, and Takenawa T.
Proteome of acidic phospholipid-binding proteins: Spatial and temporal regulation of coronin 1A by phosphoinositides.
J. Biol. Chem., 285: 6781-6789, 2010.

Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, Beutler B, and Miyake K.
Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells towards DNA- but against RNA-sensing.
J. Exp. Med., 206: 1339-1350, 2009.

Oyama M^#. (^# ; corresponding author)
Comprehensive description of signal transduction networks by quantitative proteomics and systems biology.
Curr. Bioinform., 4: 149-153, 2009.

Oyama M^*#, Kozuka-Hata H^*, Tasaki S, Semba K, Hattori S, Sugano S, Inoue J, and Yamamoto T. (^* ; equal contribution) (^# ; corresponding author)
Temporal perturbation of tyrosine-phosphoproteome dynamics reveals the system-wide regulatory networks.
Mol. Cell. Proteomics, 8: 226-231, 2009.

Nagashima T^*, Oyama M^*, Kozuka-Hata H, Yumoto N, Sakaki Y, and Hatakeyama M. (^* ; equal contribution)
Phosphoproteome and transcriptome analyses of ErbB ligand-stimulated MCF-7 cells.
Cancer Genomics Proteomics, 5: 161-168, 2008.

Hagiwara K, Sato H, Inoue Y, Watanabe A, Yoneda M, Ikeda F, Fujita K, Fukuda H, Takamura C, Kozuka-Hata H, Oyama M, Sugano S, Ohmi S, and Kai C.
Phosphorylation of measles virus nucleoprotein upregulates the transcriptional activity of minigenomic RNA.
Proteomics, 8: 1871-1879, 2008.

Mathivanan S, Ahmed M, Ahn NG, Alexandre H, Amanchy R, Andrews PC, Bader JS, Balgley BM, Bantscheff M, Bennett KL, Bjorling E, Blagoev B, Bose R, Brahmachari SK, Burlingame AS, Bustelo XR, Cagney G, Cantin GT, Cardasis HL, Celis JE, Chaerkady R, Chu F, Cole PA, Costello CE, Cotter RJ, Crockett D, DeLany JP, De Marzo AM, DeSouza LV, Deutsch EW, Dransfield E, Drewes G, Droit A, Dunn MJ, Elenitoba-Johnson K, Ewing RM, Van Eyk J, Faca V, Falkner J, Fang X, Fenselau C, Figeys D, Gagne P, Gelfi C, Gevaert K, Gimble JM, Gnad F, Goel R, Gromov P, Hanash SM, Hancock WS, Harsha HC, Hart G, Hays F, He F, Hebbar P, Helsens K, Hermeking H, Hide W, Hjern? K, Hochstrasser DF, Hofmann O, Horn DM, Hruban RH, Ibarrola N, James P, Jensen ON, Jensen PH, Jung P, Kandasamy K, Kheterpal I, Kikuno RF, Korf U, K?rner R, Kuster B, Kwon MS, Lee HJ, Lee YJ, Lefevre M, Lehvaslaiho M, Lescuyer P, Levander F, Lim MS, L?bke C, Loo JA, Mann M, Martens L, Martinez-Heredia J, McComb M, McRedmond J, Mehrle A, Menon R, Miller CA, Mischak H, Mohan SS, Mohmood R, Molina H, Moran MF, Morgan JD, Moritz R, Morzel M, Muddiman DC, Nalli A, Navarro JD, Neubert TA, Ohara O, Oliva R, Omenn GS, Oyama M, Paik YK, Pennington K, Pepperkok R, Periaswamy B, Petricoin EF, Poirier GG, Prasad TS, Purvine SO, Rahiman BA, Ramachandran P, Ramachandra YL, Rice RH, Rick J, Ronnholm RH, Salonen J, Sanchez JC, Sayd T, Seshi B, Shankari K, Sheng SJ, Shetty V, Shivakumar K, Simpson RJ, Sirdeshmukh R, Siu KW, Smith JC, Smith RD, States DJ, Sugano S, Sullivan M, Superti-Furga G, Takatalo M, Thongboonkerd V, Trinidad JC, Uhlen M, Vandekerckhove J, Vasilescu J, Veenstra TD, Vidal-Taboada JM, Vihinen M, Wait R, Wang X, Wiemann S, Wu B, Xu T, Yates JR, Zhong J, Zhou M, Zhu Y, Zurbig P, and Pandey A.
Human Proteinpedia enables sharing of human protein data.
Nat. Biotechnol., 26:164-167, 2008.

Hoshina N, Tezuka T, Yokoyama K, Kozuka-Hata H, Oyama M, and Yamamoto T.
Focal adhesion kinase regulates laminin-induced oligodendroglial process outgrowth.
Genes Cells, 12: 1245-1254, 2007.

Oyama M^#, Kozuka-Hata H, Suzuki Y, Semba K, Yamamoto T, and Sugano S. (^# ; corresponding author)
Diversity of translation start sites may define increased complexity of the human short ORFeome.
Mol. Cell. Proteomics, 6: 1000-1006, 2007.

Saito A^*, Nagasaki M^*, Oyama M^*, Kozuka-Hata H, Semba K, Sugano S, Yamamoto T, and Miyano S. (^* ; equal contribution)
AYUMS: an algorithm for completely automatic quantitation based on LC-MS/MS proteome data and its application to the analysis of signal transduction.
BMC Bioinformatics, 8: 15, 2007.

Takeda J, Suzuki Y, Nakao M, Barrero RA, Koyanagi KO, Jin L, Motono C, Hata H, Isogai T, Nagai K, Otsuki T, Kuryshev V, Shionyu M, Yura K, Go M, Thierry-Mieg J, Thierry-Mieg D, Wiemann S, Nomura N, Sugano S, Gojobori T, and Imanishi T.
Large-scale identification and characterization of alternative splicing variants of human gene transcripts using 56,419 completely sequenced and manually annotated full-length cDNAs.
Nucleic Acid Res., 34: 3917-3928, 2006.

Tasaki S^*, Nagasaki M^*, Oyama M, Hata H, Ueno K, Yoshida R, Higuchi T, Sugano S, and Miyano S. (^* ; equal contribution)
Modeling and Estimation of Dynamic EGFR Pathway by Data Assimilation Approach using Time Series Proteomic Data.
Genome Inform., 17: 226-238, 2006.

Oyama M, Itagaki C, Hata H, Suzuki Y, Izumi T, Natsume T, Isobe T, and Sugano S.
Analysis of small human proteins reveals the translation of upstream open reading frames of mRNAs.
Genome Res., 14: 2048-2052, 2004.

Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, and Sugano S.
Complete sequencing and characterization of 21,243 full-length human cDNAs.
Nat. Genet., 36: 40-45, 2004.

Suzuki Y, Taira H, Tsunoda T, Mizushima-Sugano J, Sese J, Hata H, Ota T, Isogai T, Tanaka T, Morishita S, Okubo K, Sakaki Y, Nakamura Y, Suyama A, and Sugano S.
Diverse transcriptional initiation revealed by fine, large-scale mapping of mRNA start sites.
EMBO Rep., 2: 388-393, 2001.

Suzuki Y, Tsunoda T, Sese J, Taira H, Mizushima-Sugano J, Hata H, Ota T, Isogai T, Tanaka T, Nakamura Y, Suyama A, Sakaki Y, Morishita S, Okubo K, and Sugano S.
Identification and characterization of the potential promoter regions of 1031 kinds of human genes.
Genome Res., 11: 677-684, 2001.

Oyama M, Ikeda T, Lim T, Ikebukuro K, Masuda Y, and Karube I.
Detection of toxic chemicals with high sensitivity by measuring the quantity of induced P450 mRNAs based on surface plasmon resonance.
Biotechnol. Bioeng., 71: 217-222, 2000-2001.

Lim T, Oyama M, Ikebukuro K, and Karube I.
Detection of atrazine based on the SPR determination of P450 mRNA levels in Saccharomyces cerevisiae.
Anal. Chem., 72: 2856-2860, 2000.

Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, Watanabe M, Komatsu T, Ota T, Isogai T, Suyama A, and Sugano S.
Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries.
Genomics, 64: 286-297, 2000.


日本語総説、著書

尾山 大明、秦 裕子「リン酸化時系列情報から見えるシグナルダイナミクス」
実験医学 vol 27, No.16, 2576-2581, 2009.

尾山 大明「翻訳開始点の多様性はヒトの短いORFの複雑な全体像を規定する」
実験医学 vol.25, No.18, 2895-2898, 2007.

尾山 大明他（共著、武部啓編）
ゲノム・疾患用語ハンドブック. メディカルレビュー社、2002.