Protein kinase signaling and malignant cell proliferation

• Project/Area Number: 17014030
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2008-2009); Tokyo Medical and Dental University (2005-2007)
• Principal Investigator: YAMANASHI Yuji The University of Tokyo, 医科学研究所, 教授 (40202387)
• Co-Investigator(Kenkyū-buntansha): HIGUCHI Osamu 東京大学, 医科学研究所, 准教授 (50361720) ; MASHIMA Ryuichi 東京大学, 医科学研究所, 助教 (00401365)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥72,100,000 (Direct Cost: ¥72,100,000); Fiscal Year 2009: ¥14,400,000 (Direct Cost: ¥14,400,000); Fiscal Year 2008: ¥14,400,000 (Direct Cost: ¥14,400,000); Fiscal Year 2007: ¥14,500,000 (Direct Cost: ¥14,500,000); Fiscal Year 2006: ¥14,500,000 (Direct Cost: ¥14,500,000); Fiscal Year 2005: ¥14,300,000 (Direct Cost: ¥14,300,000)
• Keywords: シグナル伝達 / 蛋白質 / 細胞・組織 / 癌 / シグナル会達

Research Abstract

To understand protein kinase signaling involved in malignant transformation of cells, we focused on the Dok-family of adaptor proteins. Our findings together revealed that Dok-1, Dok-2, and Dok-3 negatively regulate proliferation of hematopoietic cells and suppress aggressive histiocytic sarcoma. In addition, we found that Dok-7 is an essential cytoplasmic activator of the receptor protein-tyrosine kinase MuSK, proposing a novel mechanism of receptor kinase activation.

Research Products

• [Journal Article] Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive hisitocytic sarcoma. (2010)
  • Author(s): Ryuichi Mashima, Honda Kazuho, Yi Yang, Yohei Morita, Akane Inoue, Sumimasa Arimura, Hiroshi Nishina, Hideo Ema, Hiromitsu Nakauchi, Brian Seed, Hideaki Oda, Yuji Yamanashi.
  • Journal Title: Lab.Investigation 90 Pages: 1357-1364
  • Peer Reviewed
• [Journal Article] Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma. (2010)
  • Author(s): Mashima R, Honda K, Yang Y, Morita Y, Inoue A, Arimura S, Nishina H, Ema H, Nakauchi H, Seed B, Oda H, Yamanashi Y
  • Journal Title: Laboratory Investigation Volume: 90 Pages: 1357-1364
  • Peer Reviewed
• [Journal Article] Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation. (2009)
  • Author(s): Akane Inoue, Kiyoko Setoguchi, Yosuke Matsubara, Kumiko Okada, Nozomi Sato, Yoichiro Iwakura, Osamu Higuchi, Yuji Yamanashi.
  • Journal Title: Science Signaling 2
  • Peer Reviewed
• [Journal Article] The roles of Dok family adaptors in immunoreceptor signaling. (2009)
  • Author(s): Ryuichi Mashima, Yukihiro Hishida, Tohru Tezuka, Yuji Yamanashi.
  • Journal Title: Immunological Reviews 232 Pages: 273-285
  • Peer Reviewed
• [Journal Article] The roles of Dok family adapters in immunoreceptor signaling (2009)
  • Author(s): Mashima R, Hishida Y, Tezuka T, Yamanashi Y
  • Journal Title: Immunological Reviews Volume: 232 Pages: 273-285
  • Peer Reviewed
• [Journal Article] Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation (2009)
  • Author(s): Akane lnoue, 他
  • Journal Title: Science Signaling 2(ra7 (インターネット雑誌))
  • Peer Reviewed
• [Journal Article] Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7. (2008)
  • Author(s): Johko Hamuro, Osamu Higuchi, Kumiko Okada, Makiko Ueno, Shun-ichiro Iemura, Tohru Natsume, Hayley Spearman, David Beeson, Yuji Yamanashi.
  • Journal Title: J.Biol.Chem. 283 Pages: 5518-5524
  • Peer Reviewed
• [Journal Article] Dok-1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPARg phosphorylation. (2008)
  • Author(s): Tetsuya Hosooka, Tetsuya Noguchi, Ko Kotani, Takehiro Nakamura, Hiroshi Sakaue, Hiroshi Inoue, Wataru Ogawa, Kazutoshi Tobimatsu, Kazuo Takazawa, Mashito Sakai, Yasushi Matsuki, Ryuji Hiramatsu, Tomoharu Yasuda, Mitchell A.Lazar, Yuji Yamanashi, Masato Kasuga.
  • Journal Title: Nature Med. 14 Pages: 188-193
  • Peer Reviewed
• [Journal Article] Dok-7/MuSK signaling and a congenital myasthenic syndrome. (2008)
  • Author(s): Yuji Yamanashi, Osamu Higuchi, David Beeson.
  • Journal Title: Acta Myologica 27 Pages: 25-29
  • Peer Reviewed
• [Journal Article] Mutations causing DOK7 congenital myasthenia ablate functional motifsin Dok-7 (2008)
  • Author(s): Johko Hamuro, 他
  • Journal Title: Journal of Biological Chemistry 283 Pages: 5518-5524
  • Peer Reviewed
• [Journal Article] Dok-1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPARγ phosphorylation (2008)
  • Author(s): Tetsuya Hosooka, 他
  • Journal Title: Nature Medicine 14 Pages: 188-193
  • Peer Reviewed
• [Journal Article] Dok-1 is a positive regulator of IL-4 signaling and IgE response. (2007)
  • Author(s): Akane Inoue, Tomoharu Yasuda, Tadashi Yamamoto, Yuji Yamanashi.
  • Journal Title: J.Biochemistry 142 Pages: 257-263
  • NAID: 10020097405
  • Peer Reviewed
• [Journal Article] Clinical features of the DOK7 neuromuscular junction synaptopathy. (2007)
  • Author(s): Jacqueline Palace, Daniel Lashley, John Newsom-Davis, Judy Cossins, Susan Maxwell, Robin Kennett, Sandeep Jayawant, Yuji Yamanashi, David Beeson.
  • Journal Title: Brain 130 Pages: 1507-1515
  • Peer Reviewed
• [Journal Article] Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. (2007)
  • Author(s): Tomoharu Yasuda, Kenji Bundo, Ayako Hino, Kazuho Honda, Akane Inoue, Masaki Shirakata, Mitsujiro Osawa, ToshikiTamura, Hideo Nariuchi, Hideaki Oda, Tadashi Yamamoto, Yuji Yamanashi.
  • Journal Title: Int.Immunology 19 Pages: 487-495
  • NAID: 10020110607
  • Peer Reviewed
• [Journal Article] The adaptor-like protein ROG-1 is required for activation of the Ras-MAP kinase pathway and meiotic cell cycle progression in Caenorhabditis elegans. (2007)
  • Author(s): Yosuke Matsubara, Ichiro Kawasaki, Seiichi Urushiyama, Tomoharu Yasuda, Masaki Shirakata, Yuichi Iino, Hiroshi Shibuya, Yuji Yamanashi.
  • Journal Title: Genes Cells 12 Pages: 407-420
  • Peer Reviewed
• [Journal Article] Dok-1 is a positive regulator of IL-4 signaling and IgE response (2007)
  • Author(s): Akane Inoue, 他
  • Journal Title: Journal of Biochemistry 142 Pages: 257-263
  • Peer Reviewed
• [Journal Article] Dok-1 and Dok-2 are negative regulators of T Cell Receptor Signaling (2007)
  • Author(s): Tomoharu Yasuda 他
  • Journal Title: International Immunology (in press)
• [Journal Article] The adaptor-like protein ROG-1 is required for activation of the RAS-MAP kinase pathway and meiotic cell cycle progression in Caenoharbditis elegans (2007)
  • Author(s): Yosuke Matsubara 他
  • Journal Title: Genes to Cells 12 Pages: 407-420
• [Journal Article] Dok-7 mutations underlie a neuromuscular junction synaptopathy. (2006)
  • Author(s): David Beeson, Osamu Higuchi, Jackie Palace, Judy Cossins, Hayley Spearman, Susan Maxwell, John Newsom-Davis, Georgina Burke, Peter Fawcett, Masakatsu Motomura, Juliane S.Muller, Hanns Lochmuller, Clarke Slater, Angela Vincent, Yuji Yamanashi.
  • Journal Title: Science 313 Pages: 1975-1978
  • Peer Reviewed
• [Journal Article] The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. (2006)
  • Author(s): Kumiko Okada, Akane Inoue, Momoko Okada, Yoji Murata, Shigeru Kakuta, Takafumi Jigami, Sachiko Kubo, Hirokazu Shiraishi, Katsumi Eguchi, Masakatsu Motomura, Tetsu Akiyama, Yoichiro Iwakura, Osamu Higuchi, Yuji Yamanashi.
  • Journal Title: Science 312 Pages: 1802-1805
  • Peer Reviewed
• [Journal Article] Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases. (2006)
  • Author(s): Miyuki Honma, Osamu Higuchi, Masaki Shirakata, Tomoharu Yasuda, Hiroshi Shibuya, Shun-ichiro Iemura, Tohru Natsume, Yuji Yamanashi.
  • Journal Title: Genes Cells 11 Pages: 143-151
  • Peer Reviewed
• [Journal Article] The muscle protein Dok-7 is essential for neuromuscular synaptogenesis (2006)
  • Author(s): Kumiko Okada 他
  • Journal Title: Science 312 Pages: 1802-1805
• [Journal Article] Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein -tyrosine kinases. (2006)
  • Author(s): Honma Miyuki 他
  • Journal Title: Genes to Cells 11 Pages: 143-151
• [Journal Article] FLN29, a novel interferon-and LPS-inducible gene acting as a negative regulator of Toll-like receptor signaling. (2005)
  • Author(s): Ryuichi Mashima, Kazuko Saeki, Daisuke Aki, Yasumasa Minoda, Hiromi Takaki, Takahito Sanada, Takshi Kobayashi, Hiroyuki Aburatani, Yuji Yamanashi, Akihiko Yoshimura.
  • Journal Title: J.Biol.Chem. 280 Pages: 41289-41297
  • Peer Reviewed
• [Journal Article] Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. (2005)
  • Author(s): Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, Yuji Yamanashi.
  • Journal Title: J.Exp.Med. 201 Pages: 333-339
  • Peer Reviewed
• [Journal Article] Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signa ling. (2005)
  • Author(s): Hisaaki Shinohara
  • Journal Title: The Journal of Experimental Medicine 201 Pages: 333-339
• [Presentation] Dok-7, MuSK, and the development of the neuromuscular junction. (2009)
  • Author(s): Yuji Yamanashi
  • Organizer: In International Conference on Myasthenia Gravis (Plenary Lecture)
  • Place of Presentation: Paris, France.
  • Year and Date: 2009-12-01
• [Presentation] Activation of a receptor kinase by an adaptor-like protein upon neuromuscular synaptogenesis. (2009)
  • Author(s): Yuji Yamanashi
  • Organizer: In The 9th Korea-Japan Symposium on Cancer and Aging Research (Plenary Lecture)
  • Place of Presentation: Damyang, Korea.
  • Year and Date: 2009-03-11
• [Presentation] Dok-7/MuSK signaling and DOK7 myasthenia. (2008)
  • Author(s): Yuji Yamanashi
  • Organizer: In Symposium 4S2 of The 31st Annual Meeting of the Molecular Biology Society of Japan and The 81st Annual Meeting of the Japanese Biochemical Society (Invited)
  • Place of Presentation: Kobe, Japan.
  • Year and Date: 2008-12-12
• [Presentation] Dok-7 signaling and its defects in DOK7 myasthenia. (2008)
  • Author(s): Yuji Yamanashi
  • Organizer: In The 15th East Asia Joint Conference on Biomedical Research (Invited)
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2008-07-22
• [Presentation] Dok-7/MuSK signaling and DOK7 myasthenia. (2008)
  • Author(s): Yuji Yamanashi
  • Organizer: In Symposium 1 of the 20th meeting of the Japanese Society for Neuroimmunology (Invited)
  • Place of Presentation: Niigata, Japan.
  • Year and Date: 2008-04-17
• [Presentation] Activation of the receptor tyrosine kinase MuSK by Dok-7 and myasthenia. (2007)
  • Author(s): Yuji Yamanashi
  • Organizer: In Workshop 4W19 of The 30th Annual Meeting of the Molecular Biology Society of Japan and The 80th Annual Meeting of the Japanese Biochemical Society (Invited)
  • Place of Presentation: Yokohama, Japan.
  • Year and Date: 2007-12-14
• [Presentation] Dok-7/MuSK signaling and a congenital myasthenic syndrome. (2007)
  • Author(s): Yuji Yamanashi
  • Organizer: In The 8th Japan-Korea Symposium on Cancer and Aging Research (Invited)
  • Place of Presentation: Gifu, Japan.
  • Year and Date: 2007-08-11
• [Presentation] Dok-7/MuSK signaling and a congenital myasthenic syndrome. (2007)
  • Author(s): Yuji Yamanashi
  • Organizer: In 7th Japanese-French Workshop on "Development of Molecular Therapy toward Muscular Dystrophy" (Invited)
  • Place of Presentation: Hayama, Japan.
  • Year and Date: 2007-06-08
• [Presentation] Dok-mediated signaling in Cancer and other disorders. (2006)
  • Author(s): Yuji Yamanashi
  • Organizer: In Symposium 1 of 2006 Korean Society ofMedical Biochemistry and Molecular Biology Meeting (Invited)
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2006-10-26
• [Presentation] Roles of Dok-1 and Dok-2 in negative regulation of immune signaling. (2005)
  • Author(s): Yuji Yamanashi
  • Organizer: In Symposium 9 of 2005 General Meeting of The Japanese Society for Immunology (Invited)
  • Place of Presentation: Yokohama, Japan.
  • Year and Date: 2005-12-14
• [Presentation] Roles of the Dok-family adaptors in hematopoietic cells. (2005)
  • Author(s): Yuji Yamanashi
  • Organizer: In The 7th Korea-Japan Symposium on Cancer and Aging Research (Invited)
  • Place of Presentation: Muju, Korea.
  • Year and Date: 2005-11-04
• [Presentation] Regulation of cellular signaling by the Dok-family adaptors.
  • Author(s): Yuji Yamanashi
  • Organizer: In 15th Endotoxin and LPS Meeting (Invited).
  • Place of Presentation: Tokyo, Japan
• [Book] 受容体型キナーゼの細胞内からの活性(実験医学)、27巻(6月号) (2009)
  • Author(s): 井上茜、瀬戸口喜代子、樋口理、山梨裕司
  • Publisher: 羊土社
• [Book] Dok-7シグナルと筋無力症、(実験医学)26巻(増刊) (2008)
  • Author(s): 山梨裕司
  • Publisher: 羊土社
• [Book] 免疫機構とDok-1/2を介した抑制シグナル(Annual Review免疫2007) (2006)
  • Author(s): 山梨裕司
  • Publisher: 中外医学社
• [Book] チロシンキナーゼのシグナル伝達(実験医学)23巻(増刊) (2005)
  • Author(s): 山梨裕司
  • Publisher: 羊土社
• [Remarks] ホームページ等
  • URL: http://www.ims.u-tokyo.ac.jp/genetics/html/home.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/genetics/html/home.html
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/crew/index.html
• [Patent(Industrial Property Rights)] 筋特異的チロシンキナーゼの活性化を制御するポリペプチドをコードするDNA (2007)
  • Inventor(s): 山梨裕司, 他
  • Industrial Property Rights Holder: 東京医科歯科大学
  • Filing Date: 2007-04-26
• [Patent(Industrial Property Rights)] 筋特異的チロシンキナーゼの活性化を制御するポリペプチドをコードするDNA (2007)
  • Inventor(s): 山梨裕司、他
  • Industrial Property Rights Holder: 東京医科歯科大学
  • Filing Date: 2007-04-26
  • Overseas
• [Patent(Industrial Property Rights)] 筋特異的チロシンキナーゼの活性化を制御するポリペプチドをコードするDNA (2006)
  • Inventor(s): 山梨裕司, 他
  • Industrial Property Rights Holder: 東京医科歯科大学
  • Industrial Property Number: 2006-158987
  • Filing Date: 2006-06-07