Institute of Development, Aging and Cancer, Tohoku University


Dept. Molecular and Cellular Biology

Professor Hisanori HORIUCHI
Assistant Professor Ryutaro SHIRAKAWA
Assistant Professor Tomohiro KIMURA
Homepage of This Laboratory

Introduction of our laboratory:
We are investigating intracellular signaling focusing upon small GTPases.
By biochemical methods, we have identified several important signaling molecules implicated in several functions such as exoxytosis and oncogenesity. Especially, we are focusing on the physiological and pathological functional importance of RalGAP we have discovered (JBC, 2009).

In the research of RalGAP, we have recently published a paper in Oncogene (2013) showing that: (1) RalGAPα2 subunit that is predominantly expressed in bladder tissues was down-regulated in invasive-type bladder cancer cells. (2) Down-regulation of RalGAPα2 was associated with poor prognosis of patient survival. (3) Lung metastasis of bladder cells exogenously expressing RalGAPα2 subunit was inhibited in a mice model (4) Invasive-type bladder cancer was often developed in mice deficient in RalGAPα2 subunit while it was not developed in wild type mice in a chemical-induced bladder cancer model in mice.

Recently, we have started a novel project that is ‘elucidation of molecular mechanism of NETosis’. Neutrophils migrate to an infected tissue from blood stream. There, they eat bacteria by phagocytosis and kill them by producing reactive oxygen species (ROS). Recently, a novel response of neutrophils has been discovered. Activated neutrophils release their chromatin to extracellular space to form ‘neutrophil extracellular traps (NETs)’. NETs play an important role not only for eliminating bacteria but also thrombus formation, cancer metastasis and development of autoimmune diseases such as SLE. In addition, formation of NETs is recognized as a third type of cell death distinct from necrosis and apoptosis. In spite of medical and biological importance of NETs formation, its mechanism largely remains unclear except for involvement of PKC activation, intracellular calcium ion elevation, ROS production, and protein citrullination by the enzyme PAD4 in the process. We have started to elucidate its molecular mechanism.

Recent major publication(*: corresponding author)

  1. R. Shirakawa, H. Horiuchi (2015) Ral GTPases: crucial mediators of exocytosis and tumorigensis. (a review) J Biochem (Tokyo) in press
  2. N. Yaoita, R. Shirakawa, Y. Fukumoto, K. Sugimura, S. Miyata, Y. Miura, K. Nochioka, M. Miura, S. Tatebe, T. Aoki, S. Yamamoto, K. Satoh, T. Kimura, H. Shimokawa, H. Horiuchi (2014) Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension (CTEPH) Arteriosclerosis Thromb Vasc Biol, 34, 2486-2494
  3. T. Kimura, R. Shirakawa, N. Yaoita, T. Hayashi, K. Nagano, H. Horiuchi (2014) The antimalarial drugs chloroquine and primaquine inhibit pyridoxal kinase, an essential enzyme for vitamin B6 production. FEBS Letter 588:3673-3676
  4. Q. Chen, C. Quan, B. Xie, L. Chen, S. Zhou, R. Toth, DG Campbell, S. Lu, R. Shirakawa, H. Horiuchi, C. Li, Z. Yang, C. MacKintosh, H-Y Wang, S. Chen (2014) GARNL1, a major RalGAP alpha subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins. Cell Signal 26, 1636-1648.
  5. R Saito, R Shirakawa, H Nishiyama, T Kobayashi, M Kawato, T Kanno, K Nishizawa, Y Matsui, T Ohbayashi, M Horiguchi, T Nakamura, T Ikeda, K Yamane, E Nakayama, E Nakamura, Y Toda, T Kimura, T Kita, O Ogawa, H Horiuchi (2013) Downregulation of Ral GTPase-activating protein causes tumor invasion and metastasis of bladder cancer. Oncogene 32, 894-902
  6. K Boswell, D James, J Esquibel, S Bruinsma, R Shirakawa, H Horiuchi, T Martin (2012) Munc13-4 reconstitutes Ca2+-dependent SNARE-mediated membrane fusion. J Cell Biol 197, 301-312
  7. Yamane, T. Ikeda, R. Taniguchi, S. Watanabe, M. Kawato, H. Kondo, R. Shirakawa, T. Higashi, M. Toma, T. Tamura, A. Tabuchi, K. Takahashi, H. Watanabe, Y. Yoshikawa, T. Kita, T. Kimura, H. Horiuchi (2012) The impact of platelet reactivity on long-term clinical outcomes and bleeding complications in Japanese patients receiving antiplatelet therapy with aspirin. J Atherosclerosis Thombosis 19, 1142-1153.
  8. Y. Murata, T. Yasumi, R. Shirakawa, K. Izawa, H. Sakai, J. Abe, N. Tanaka, T. Kawai, K. Oshima, M. Saito, R. Nishikomori, O. Ohara, E. Ishii, T. Nakahata, H. Horiuchi, T. Heike (2011) Rapid diagnosis of familial hemophagocytic lymphohistiocytosis type 3 (FHL3) by flow cytometric detection of intraplatelet Munc13-4 protein. Blood 118, 1225-1230
  9. Higashi, T. Ikeda, T. Murakami, R. Shirakawa, M. Kawato, K. Okawa, M. Furuse, T. Kimura, T. Kita, H. Horiuchi (2010) Flightless-I (Fli-I) regulates the actin assembly activity of Diaphanous-related formins (DRFs), Daam1 and mDia1, in cooperation with active Rho GTPase. J Biol Chem 285, 16231-16238
  10. R. Shirakawa, S. Fukai, M. Kawato, T. Higashi, H. Kondo, T. Ikeda, E. Nakayama, K. Okawa, O. Nureki, T. Kimura, T. Kita, H. Horiuchi (2009) Tuberous sclerosis tumor suppressor complex-like complexes act as GTPase activating proteins for Ral GTPases. J Biol Chem 284, 21580-21588

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