日本学士院

会員情報

 

氏名

廣川信隆 （ひろかわ のぶたか）

 

所属部・分科

第2部第7分科

選定年月日

平成16年12月13日

専攻学科目

分子細胞生物学

現職等

東京大学名誉教授
順天堂大学健康総合科学先端研究機構特任教授
東京大学大学院医学系研究科特任研究員

受賞等

〔国内〕

上原賞（平成7年）
朝日賞（平成8年）
武田医学賞（平成10年）
藤原賞（平成11年）
日本学士院賞（平成11年）
文化功労者（平成25年）

〔海外〕

Eduard Buchner Prize （ドイツ生化学・分子生物学会）（2005年）

外国アカデミー会員等

ヨーロッパ分子生物学機構(EMBO)外国人会員（2003年）
AAAS(The American Association for the Advancement of Science)フェロー（2013年）
Honorary Degree of Medical Sciences, Honoris Causa, Charles University Czech Republic（2016年）

主要な学術上の業績

細胞内には生存と機能に必要な物質を、必要な場所に送り届けるためのモーター蛋白とレール(微小管)からなる輸送システムがあります。廣川信隆氏はモーター蛋白(KIFs)の遺伝子の殆どすべてを同定し、モーター蛋白が微小管の上を走る仕組み、それぞれのモーターが運ぶ物質の種類の選択、輸送の早さ、輸送の方向性の決定、KIFs のATP加水分解による作動機構など細胞内物質輸送の基本的な分子機構を解明し、KIFs による細胞内物質輸送が細胞機能の根底を支えていることを示しました。さらに KIFs遺伝子改変マウスの作製と解析により、分子モーターが、脳の神経回路網の形成、記憶、学習などの高次機能、体の左右非対称性の決定、腫瘍の抑制など重要な生命現象を司っていることを明らかにしました。最近では、KIFsの障害は精神・神経及び代謝疾患等多くの疾患と深く関わることを明らかにし、それら疾患の病態生理を解明して、新しい診断、治療への道を開いています。同氏はこの分野のパイオニアであり、国際的なリーダーです。

主要な著書・論文

  1. Hirokawa N.  Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J Cell Biol 94: 129-142, 1982.
  2. Hirokawa, N., K. K. Pfister, H. Yorifuji, M. C. Wagner, S. T. Brady, and G. S. Bloom.  Submolecular domains of bovine brain kinesin identified by electron microscopy and monoclonal antibody decoration. Cell 56: 867-878. 1989.(Cover)
  3. Aizawa, H., Y. Sekine, R. Takemura, Z. Zhang, M. Nangaku, and N. Hirokawa.  Kinesin family in murine central nervous system. J Cell Biol 119: 1287-1296. 1992.
  4. Nangaku, M., R. Sato-Yoshitake, Y. Okada, Y. Noda, R. Takemura, H. Yamazaki, and N. Hirokawa.  KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell 79: 1209-1220. 1994.
  5. Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa.  The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81: 769-780. 1995. (Cover)
  6. Kikkawa, M., T. Ishikawa, T. Wakabayashi, and N. Hirokawa.  Three-dimensional structure of the kinesin head-microtubule complex. Nature 376: 274-277. 1995.
  7. Terada, S., T. Nakata, A. C. Peterson, and N. Hirokawa.  Visualization of slow axonal transport in vivo. Science 273: 784-788. 1996.
  8. Hirokawa, N.  Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279: 519-526, 1998. (Cover)
  9. Tanaka, Y., Y. Kanai, Y. Okada, S. Nonaka, S. Takeda, A. Harada, and N. Hirokawa.  Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93: 1147-1158, 1998.
  10. Nonaka, S., Y. Tanaka, Y. Okada, S. Takeda, A. Harada, Y. Kanai, M. Kido, and N. Hirokawa.  Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95: 829-837, 1998.
  11. Okada, Y., and N. Hirokawa.  A Processive Single-Headed Motor: Kinesin Superfamily Protein KIF1A. Science 283: 1152-1157, 1999.
  12. Kikkawa, M., Y. Okada, and N. Hirokawa.  15 Angstrom Resolution Model of the Monomeric Kinesin Motor, KIF1A. Cell 100: 241-252, 2000.
  13. Setou, M., T. Nakagawa, D. H. Seog, and N. Hirokawa.  Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288: 1796-1802, 2000. (Cover)
  14. Terada, S., M. Kinjo, and N. Hirokawa.  Oligomeric tubulin in large transporting complex is transported via kinesin in squid giant axons. Cell 103: 141-155, 2000.
  15. Nakagawa, T., M. Setou, D. Seog, K. Ogasawara, N. Dohmae, K. Takio, and N. Hirokawa.  A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103: 569-581, 2000.
  16. Kikkawa, M., E. P. Sablin, Y. Okada, H. Yajima, R. J. Fletterick, and N. Hirokawa.  Switch-based mechanism of kinesin motors. Nature (Article)411: 439-445, 2001.
  17. Zhao, C., J. Takita, Y. Tanaka, M. Setou, T. Nakagawa, S. Takeda, H. W. Yang, S. Terada, T. Nakata, Y. Takei, M. Saito, S. Tsuji, Y. Hayashi, and N. Hirokawa.  Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105: 587-597, 2001.(Cover)
  18. Miki, H., M. Setou, K. Kaneshiro, and N. Hirokawa.  All kinesin superfamily protein, KIF, genes in mouse and human. PNAS 98: 7004-7011, 2001.
  19. Setou, M., D.-H. Seog, Y. Tanaka, Y. Kanai, Y. Takei, M. Kawagishi, and N. Hirokawa.  Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417: 83-87, 2002.
  20. Wong, R. W.-C., M. Setou, J. Teng, Y. Takei, and N. Hirokawa.  Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. PNAS 99: 14500-14505, 2002.
  21. Homma, N., Y. Takei, Y. Tanaka, T. Nakata, S. Terada, M. Kikkawa, Y. Noda, and N. Hirokawa.  Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension. Cell 114: 229-239, 2003.
  22. Okada, Y., H. Higuchi, and N. Hirokawa.  Processivity of the single-headed kinesin KIF1A through biased binding to tubulin. Nature 424: 574-577, 2003.
  23. Nakata, T. and N. Hirokawa. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J Cell Biol 162: 1045-1055, 2003.
  24. Ogawa, T., R. Nitta, Y. Okada, and N. Hirokawa.  A common mechanism for microtubule destabilizers –　M-type kinesins stabilize curling of the protofilament using the class-specific neck and loops.  Cell 116: 591-602, 2004.
  25. Nitta, R., M. Kikkawa, Y. Okada, and N. Hirokawa.              KIF1A alternately uses two loops to bind microtubules.  Science 305: 678-683, 2004.
  26. Kanai, Y., N. Dohmae, and N. Hirokawa.  Kinesin transports RNA: isolation and characterization of an RNA-transporting granule.  Neuron 43: 513-525, 2004.
  27. Hirokawa, N. and R. Takemura. Molecular motors and mechanisms of directional transport in neurons. Nature Rev Neurosci 6:201-214, 2005.
  28. Teng J., T. Rai, Y. Tanaka, Y. Takei, T. Nakata, M. Hirasawa, A. B. Kulkarni, and N. Hirokawa. The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium. Nature Cell Biol 7: 474-482, 2005.
  29. Tanaka, Y., Y. Okada, and N. Hirokawa.  FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature (Article)435:172-177, 2005.
  30. Okada, Y., S. Takeda, Y. Tanaka, J.-C. I. Belmonte and N. Hirokawa. Mechanism of nodal flow: a conserved symmetry breaking event in left-right axis determination. Cell 121:633-644, 2005.
  31. Hirokawa, N., Y. Tanaka, Y. Okada and S. Takeda.   Nodal flow and the generation of left-right asymmetry.  Cell 125: 33-45, 2006.
  32. Midorikawa R., Y. Takei, and N. Hirokawa.  KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity.  Cell 125: 371-383, 2006. 
  33. Guillaud, L., R. Wong and N. Hirokawa. Disruption of KIF17-Mint1 interaction by CamKII-dependent phosphorylation: a molecular model of kinesin-cargo release. Nature Cell Biol 10: 19-29, 2008.
  34. Nitta, R., Y. Okada and N. Hirokawa. Structural model for strain-dependent microtubule activation of Mg-ADP release from kinesin. Nature Str & Mol Biol 15 : 1067-1075, 2008.
  35. Niwa, S., Y. Tanaka and N. Hirokawa. KIF1Bbeta- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD.  Nature Cell Biol 11: 1269-1276, 2008.
  36. Hirokawa, N., Y. Noda, Y. Tanaka, and S. Niwa. Kinesin superfamily motor proteins and intracellular transport. Nature Revs Mol Cell Biol 10: 682-696, 2009. (Cover)
  37. Zhou R., S. Niwa, N. Homma, Y. Takei, and N. Hirokawa.  KIF26A is an unconventional kinesin and regulates GDNF-Ret signaling in enteric neuronal development. Cell 139: 802-813, 2009.
  38. Hirokawa, N., R. Nitta and Y. Okada.  The mechanisms of kinesin motor motility: lessons from the monomeric motor KIF1A.  Nature Rev Mol Cell Biol 10: 877-884, 2009.(Cover)
  39. Hirokawa, N., S. Niwa and Y. Tanaka. Molecular motors in neurons: Transport mechanisms and roles in brain function, development, and disease. Neuron 68: 610-638, 2010.
  40. Yin, X., Y. Takei, M. A. Kido and N. Hirokawa. Molecular motor KIF17 is fundamental for memory and learning via differential support of synaptic NR2A/2B levels. Neuron 70: 310-325, 2011. DOI 10.1016/j.neuron.2011.02.049
  41. Nakata, T., S. Niwa, Y. Okada, F. Perez, and N. Hirokawa. Preferential binding of a kinesin-1 motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport. J Cell Biol 194：245-255, 2011. DOI: 10.1083/jcb.201104034
  42. Kondo, M., Y. Takei, and N. Hirokawa.  Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment. Neuron 73: 743-757, 2012. DOI 10.1016/j.neuron.2011.12.020
  43. Niwa, S., K. Nakajima, H.Miki, Y. Minato, D. Wang, and N. Hirokawa.  KIF19A is a microtubule-depolymerizing kinesin for ciliary length control. Dev Cell 23: 1167-1175, 2012. doi.org/10.1016/j.devcel.2012.10.016.
  44. Nakajima, K., X. Yin, Y. Takei, D.-H. Seog, N. Homma, N. Hirokawa. Molecular motor KIF5A is essential for GABAA receptor transport, and KIF5A deletion causes epilepsy. Neuron 76: 945-961, 2012. doi.org/10.1016/j.neuron.2012.10.012.
  45. Zhou, R., S. Niwa, L. Guillaud, Y. Tong, and N. Hirokawa. A molecular motor, KIF13A, controls anxiety by transporting the serotonin type 1A receptor. Cell Rep 3: 509-519, 2013. http://dx.doi.org/10.1016/j.celrep.2013.01.014.
  46. Kanai, Y., D. Wang and N. Hirokawa.  KIF13B enhances the endocytosis of LRP1 by recruiting LRP1 to caveolae. J Cell Biol 204: 395–408, 2014.  doi:10.1083/jcb.201309066.
  47. Yang, W., Y. Tanaka, M. Bundo, and N. Hirokawa.  Antioxidant signaling involving the microtubule motor KIF12 is an intracellular target of nutrition excess in beta cells. Dev Cell 31: 202–214, 2014. DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.028
  48. Ichinose, S., T. Ogawa, and N. Hirokawa. Mechanism of Activity-dependent Cargo Loading via the Phosphorylation of KIF3A by PKA and CaMKIIa.  Neuron 87: 1022–1035, 2015.　 DOI:10.1016/j.neuron.2015.08.008
  49. Tanaka, Y., S. Niwa, M. Dong, A. Farkhondeh, L. Wang, R. Zhou, and N. Hirokawa.  The molecular motor KIF1A transports the TrkA neurotrophin receptor and is essential for sensory neuron survival and function. Neuron 90: 1215–1229, 2016. http://dx.doi.org/10.1016/j.neuron.2016.05.002.
  50. Wang, D., R. Nitta, M. Morikawa, H. Yajima, S. Inoue, H. Shigematsu, M. Kikkawa, and N. Hirokawa.  Motility and microtubule depolymerization mechanisms of the kinesin-8 motor, KIF19A.  eLife 2016 https://elifesciences.org/content/5/e18101
  51. Homma, N., R. Zhou, M. I. Naseer, A. G Chaudhary, M. H Al-Qahtani, and N. Hirokawa.  KIF2A regulates the development of dentate granule cells and postnatal hippocampal wiring. eLife 2018;7:e30935.  https://doi.org/10.7554/eLife.30935.
  52. Wang, L., Y. Tanaka, D. Wang, M. Morikawa, R. Zhou, N. Homma, Y. Miyamoto, and N. Hirokawa.  The atypical kinesin KIF26A facilitates termination of nociceptive responses by sequestering focal adhesion kinase. Cell Rep 11: 2894-2907, 2018. doi: 10.1016/j.celrep.2018.05.075..
  53. Morikawa, Mo., Y. Tanaka, H-S. Cho, M. Yoshihara, and N. Hirokawa. The molecular motor KIF21B mediates synaptic plasticity and fear extinction by terminating Rac1 activation.  Cell Rep 23: 3864-3877, 2018. Https://doi.org/10.1016/j.celrep.2018.05.089
  54. Fang, Xu. H. Takahashi, Y. Tanaka, S. Ichinose, S. Niwa, M.P.Wicklund, and N. Hirokawa.   KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth.  J Cell Biol 217: 3480-3496, 2018.  https://doi.org/10.1083/jcb.201801085.
  55. Shima, T*., Ma. Morikawa*, J. Kaneshiro, T. Kambara, S. Kamimura, T. Yagi, H. Iwamoto, S. Uemura, H. Shigematsu, M. Shirouzu, T. Ichimura, T. M. Watanabe, R. Nitta, Y. Okada, and N. Hirokawa.  Kinesin-binding–triggered conformation switching of microtubules contributes to polarized transport. J Cell Biol 217: 4164–4183, 2018.http://doi.org/10.1083/jcb.201711178 * equal contribution
  56. Alsabban, AH.*, Mo. Morikawa*, Y. Tanaka, Y. Takei, and N. Hirokawa.  Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.  EMBO J  Nov 20:e101090. 2019 doi: 10.15252/embj.2018101090. * equal contribution
  57. Iwata, S.,Mo. Morikawa, Y. Takei, and N. Hirokawa. An activity-dependent local transport regulation via degeneration and synthesis of KIF17 underlying cognitive flexibility. Science Advs.2020; 6:eabc8355(published on line: 16 Dec 2020)
  58. Yoshihara, S.,X. Jiang, Mo. Morikawa,-----------and N. Hirokawa. Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport. Cell Rep 35, 108971, 2021 https://doi.org/10.1016/j. celrep.2021. 108971
  59. Morikawa,M. , N. Jerath , T. Ogawa , Mo. Morikawa , Y. Tanaka , M. E. Shy , S. Zuchner and N. Hirokawa.  A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle. EMBO J　2022 41:e108899 https://doi.org/10.15252/embj.2021108899
  60. Wang, S.*, Y. Tanaka*, Y. Xu, S. Takeda, and N. Hirokawa. KIF3B promotes a PI3K signaling gradient causing changes in a Shh protein gradient and suppressing polydactyly in mice. Dev Cell 57: 2273-2289,2022 * equal contribution (Cover)https://doi.org/10.1016/j.devcel.2022.09.007
  61. Wan, Y., Mo. Morikawa, M. Morikawa, S. Iwata, M.I. Naseer, A.G. Chaudhary, Y. Tanaka, and N. Hirokawa. KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway. J Cell Biol 222: e202208108, 2023https://doi.org/10.1083/jcb.2022208108
  62. Tanaka, Y.,A. Morozumi, and N.Hirokawa. Nodal flow transfers polycystin to determine mouse left-right asymmetry. Dev Cell 58:1447-1461, 2023 https://doi.org/10.1016/j.devcel.2023.06.002

リンク

http://cb.m.u-tokyo.ac.jp/