神経・腫瘍のシグナル解析プロジェクト研究部門
神経・腫瘍のシグナル解析プロジェクト部門ホームページ
生体内で細胞は、細胞内外の情報を受け取り、隣り合う細胞や細胞外の基質と接着することで、特有の形態を呈し極性を獲得している。これらの過程は細胞が臓器や組織で特有の機能を発揮するために必須であり、生命活動の根本とも言える。これらの過程に異常が生じると精神神経疾患、癌、循環器疾患など多様な疾患が引き起こされる。すなわち、細胞形態、運動、接着、極性の制御機構を解明することは、生物の基本的な成り立ちを明らかにするだけでなく、様々な疾患の原因や治療法を確立する上で欠くことができない。我々の研究室では、細胞の形態、運動、接着、極性の分子機構を解明することにより、精神神経疾患、癌、循環器疾患の病態を細胞レベルから解き明かすことを目標にしている。
研究内容
1. 細胞形態を制御する分子機構の解析
生体内で細胞は、細胞内外の情報を受け取り、隣り合う細胞や細胞外の基質と接着することで、特有の形態を呈し極性を獲得している。これらの過程は、細胞が臓器や組織で特有の機能を発揮するために必須であり、生命活動の根本とも言える。これらの過程に異常が生じると精神神経疾患、癌、循環器疾患など多様な疾患が引き起こされる。すなわち、細胞形態、運動、接着、極性の制御機構を解明することは、様々な疾患の治療法を確立する上で欠くことができない。我々の研究室では、低分子量G蛋白質Rhoファミリーが細胞の形態変化、運動能、接着能、極性形成に重要な役割を担っていることを見出し、その活性制御機構や作用機序を解明することを目標としている。Rac、Cdc42、Rhoを始めとするRhoファミリーは、活性型と不活性型をサイクルすることにより細胞内で分子スイッチとして機能している。Rhoファミリーの活性は、数種の活性制御因子により厳密に制御されている。活性型のRhoファミリーは、特異的な標的蛋白質を介して多様な生理機能を発揮する。我々の研究室では生化学的手法によりRhoファミリーの標的蛋白質を多数同定し、分子生物学や細胞生物学的手法を用いてその生理機能を解析している。
2. 神経細胞の極性・回路網形成
神経細胞は脳内において複雑なネットワークを形成するが、その基本機能は信号を受け取り統合して他の細胞に伝えることである。そのため、神経細胞は分化の過程で、通常一本の軸索と複数の樹状突起を形成し、樹状突起から信号を入力して軸索から信号を出力するという極性を獲得する。しかし、神経細胞の極性がいかにして形成されるのかは長らく不明であった。我々は、細胞がどのようにしてこのような「極性」を確立するか、その分子メカニズムの解明を目指している。
3. 精神疾患の病態解明と治療法の開発
統合失調症は、生涯発症率が約１%と頻度が高く、難治例も数多く存在する重篤な精神障害である。統合失調症の発症の分子機構は現在なお不明であり、治療の分子標的は定まっていない。近年、中枢神経系の発達障害が発症仮説として有力と考えられている。また統合失調症は遺伝因子と共に、胎生期、周産期、思春期などの環境要因の双方が発症に関与する多因子疾患である。比較的進んでいる近年のゲノム解析により、統合失調症の発症脆弱性遺伝子が複数報告されている。その中でもDISC1は遺伝子家系解析で最も有力な原因遺伝子と考えられている。我々の研究室では、発症脆弱性因子間を結ぶシグナルネットワークに着目し、ネットワークを構成するシグナルタンパク質の遺伝子の神経細胞内での分子間相互作用を網羅的に解析することにより，統合失調症の病態や発症のメカニズムを明らかにすることを目標に研究を行なっている。
4. 情動行動・学習の制御機構の解明
快・不快、恐怖などの情動はモノアミン系神経により制御されていることが知られており、モノアミン系神経による報酬系は線虫からヒトまで幅広く保存されている。モノアミンやグルタミン酸の細胞内シグナルの一部が明らかになりつつあるが、情動行動・学習に関連する細胞内シグナルについては不明な点が多く残っている。我々は、情動行動・学習の制御機構を理解するための情報基盤を構築することを目的とし、関連する神経回路の動作原理や再編を制御するメカニズムの一端を明らかにすることを目標としている。最近、我々は、新たに開発したリン酸化プロテオミクス法により、マウスの側坐核で起こるリン酸化シグナルを網羅的に解析し、ドーパミンの下流でリン酸化される蛋白質を100種類以上同定した(Amano et al. J Cell Biol 2015; Nagai et al. Neuron 2016)。それらの情報を基に、ドーパミンが中型有棘神経細胞のD1受容体-プロテインキナーゼA(PKA)経路を介して低分子量G蛋白質Rap1を活性化することを明らかにした(Nagai et al. Neuron 2016)。さらに、Rap1がmitogen activated protein kinase(MAPK)とKチャネルを介して神経細胞の興奮性を高め、グルタミン酸神経伝達への応答性が上昇する結果、神経細胞が発火して快情動行動が発現することも見出している。さらに、これらリン酸化基質の情報を管理するデータベース(KANPHOS, https://kanphos.neuroinf.jp)を作成し公開している(Nagai et al, Trends Pharmacol Sci, 2016)。
代表的な業績
1. Ariza, A., Funahashi, Y., Kozawa, S., Faruk, MO., Nagai, T., Amano, M., Kaibuchi, K. Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK. J Neurochem. 157(6):1774-1788 .(2021)
2. Lin, YH., Yamahashi, Y., Kuroda, K., Faruk, MO., Zhang, X., Yamada, K., Yamanaka, A., Nagai, T., Kaibuchi, K. Accumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. Neurochem Int. 143, 104935. (2021)
3. Chowdhury, MIH., Nishioka, T., Mishima, N., Ohtsuka, T., Kaibuchi, K., and Tsuboi, D. Prickle2 and Igsf9b coordinately regulate the cytoarchitecture of the axon initial segment. Cell Struct Funct. 45(2):143-154. (2020)
4. Funahashi, Y., Watanabe, T., and Kaibuchi, K. Advances in defining signaling networks for the establishment of neuronal polarity. Curr Opin Cell Biol. 63, 76-87. (2020)
5. Funahashi, Y., Ariza, A., Emi, R., Xu, Y., Shan, W., Suzuki, K., Kozawa, S., Ahammad, RU., Wu, M., Takano, T., Yura, Y., Kuroda, K., Nagai, T., Amano, M., Yamada, K., and Kaibuchi, K. Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors. Cell Rep. 29, 10, 3235-3252. (2019)
6. Zhang, X., Nagai, T., Ahammad, RU., Kuroda, K., Nakamuta, S., Nakano, T., Yukinawa, N., Funahashi, Y., Yamahashi, Y., Amano, M., Yoshimoto, J., Yamada, K., Kaibuchi, K. Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons. Neurochem Int. 122, 8-18. (2019)
7. Takano, T., Funahashi, Y., and Kaibuchi, K. Neuronal Polarity: Positive and Negative Feedback Signals. Front Cell Dev Biol. 7, 69. (2019)
8. Nishioka, T., Amano, M., Funahashi, Y., Tsuboi, D., Yamahashi, Y., and Kaibuchi, K. In Vivo Identification of Protein Kinase Substrates by Kinase-Oriented Substrate Screening (KIOSS). Curr Protoc Chem Biol. 11, 1, e60. (2019)
9. Amano, M., Nishioka, T., Tsuboi, D., Kuroda, K., Funahashi, Y., Yamahashi, Y., and Kaibuchi, K. Comprehensive analysis of kinase-oriented phospho-signalling pathways. J Biochem. 165, 4, 301-307. (2019)
10. Takano, T., Wu, M., Nakamuta, S., Honda, N., Ishizawa, N., Namba, T., Watanabe, T., Xu, C., Hamaguchi, T., Yura, Y., Amano, M., Hahn, K., and Kaibuchi, K. Discovery of Long-Range Inhibitory Signaling to Ensure Single Axon Formation. Nat commun. 8(1):33. (2017)
11. Nagai, T., Yoshimoto, J., Kannon, T., Kuroda, K., and Kaibuchi, K. Phosphorylation signals in striatal medium spiny neurons. Trend Pharmacol Sci. 37(10):858-71. (2016)
12. Nagai, T., Nakamuta, S., Kuroda, K., Nakauchi, S., Nishioka, T., Takano, T., Zhang, X., Tsuboi, D., Funahashi, Y., Nakano, T., Yoshimoto, J., Kobayashi, K., Uchigashima, M., Watanabe, M., Miura, M., Nishi, A., Kobayashi, K., Yamada, K., Amano, M., and Kaibuchi, K. Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo. Neuron. 89(3):550-565. (2016)
13. Matsuzawa, K., Akita, H., Watanabe, T., Kakeno, M., Matsui, T., Wang, S., and Kaibuchi, K. PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions. Mol Biol Cell. 27(9):1511-1523. (2016)
14. Amano, M., Hamaguchi, T., Shohag, MH., Kozawa, K., Kato, K., Zhang, X., Yura, Y., Matsuura, Y., Kataoka, C.,Nishioka, T., and Kaibuchi, K. Kinase-interacting substrate screening is a novel method to identify kinase substrates. J Cell Biol. 209(6), 895-912. (2015)
15. Tsuboi, D., Kuroda, K., Tanaka, M., Namba, T., Iizuka, Y., Taya, S., Shinoda, T., Hikita, T., Muraoka, S., Iizuka, M.,Nimura, A., Mizoguchi, A., Shiina, N., Sokabe, M., Okano, H., Mikoshiba, K., and Kaibuchi, K. Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosci. 18(5), 698-707. (2015)
16. Namba, T., Funahashi, Y., Nakamuta, S., Xu, C., Takano, T., and Kaibuchi, K. Extracellular and Intracellular Signaling for Neuronal Polarity. Physiol Rev. 95(3), 995-1024. (2015)
17. Xu,C., Funahashi, Y., Watanabe, T., Takano,T., Nakamuta, S., Namba, T., and Kaibuchi, K. Radial glial cell-neuron interaction directs axon formation at the opposite side of the neuron from the contact site. J Neurosci. 35(43):14517-14532. (2015)
18. Watanabe, T., Kakeno, M., Matsui, T., Sugiyama, I., Arimura, N., Matsuzawa, K., Shirahige, A., Ishidate, F., Nishioka, T., Taya, S., Hoshino, M., and Kaibuchi, K. TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation. J Cell Biol. 210(5):737-751. (2015)
19. Matsui, T., Watanabe, T., Matsuzawa, K., Kakeno, M., Okumura, N., Sugiyama, I., Itoh,N., and Kaibuchi, K. PAR3 and aPKC regulate Golgi organization through CLASP2 phosphorylation to generate cell polarity. Mol Biol Cell. 26(4):751-761. (2015)
20. Takano, T., Xu, C., Funahashi, Y., Namba, T., and Kaibuchi, K. Neuronal polarization. Development. 142(12):2088-2093. (2015)
21. Shohag, MH., Nishioka, T., Ahammad, RU., Nakamuta, S., Yura, Y., Hamaguchi, T, Kaibuchi, K., and Amano, M. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters. Cell Struct Funct. 40(2):95-104. (2015)
22. Hamaguchi, T., Nakamuta, S., Funahashi, Y., Takano, T., Nishioka, T., Hasanuzzaman, SM., Yura, Y., Kaibuchi, K., and Amano, M. In vivo Screening for Substrates of Protein Kinase A using a combination of proteomic approaches and pharmacological modulation of kinase activity. Cell Struct Funct. 40(1):1-12. (2015)
23. Namba, T., Kibe, Y., Funahashi, Y., Nakamuta, S., Takano, T., Ueno, T., Shimada, A., Kozawa, S., Okamoto, M., Shimoda, Y., Oda, K., Wada, Y., Masuda, T., Sakakibara, A., Igarashi, M., Miyata, T., Faivre-Sarrailh, C., Takeuchi, K., and Kaibuchi, K. Pioneering axons regulate neuronal polarization in the developing cerebral cortex. Neuron. 81, 814-829. (2014)
24. Funahashi, Y., Namba, T., Nakamuta, S., and Kaibuchi, K. Neuronal polarization in vivo: Growing in a complex environment. Neuronal polarization in vivo: Growing in a complex environment. Curr Opin Neurobiol. 27:215-223. (2014)
25. Kakeno, M., Matsuzawa, K., Matsui, T., Akita, H., Sugiyama, I., Ishidate, F., Nakano, A., Takashima, S., Goto, H., Inagaki, M., Kaibuchi. K., and Watanabe, T. Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment. Cell Struct Funct. 9(1):45-59. (2014)
26. Funahashi, Y., Namba, T., Fujisue, S., Itoh, N., Nakamuta, S., Kato, K., Shimada, A., Xu, C., Shan, W., Nishioka, T., and Kaibuchi, K. ERK2-mediated phosphorylation of Par3 regulates neuronal polarization. J Neurosci. 33, 13270-13285. (2013)
27. Nakayama, M., Nakayama, A., van Lessen, M., Yamamoto, H., Hoffmann, S., Drexler, HC., Itoh, N., Hirose, T., Breier, G., Vestweber, D., Cooper, JA., Ohno, S., Kaibuchi, K., and Adams, RH. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat Cell Biol. 15(3):249-260. (2013)
28. Wang, S., Watanabe, T., Matsuzawa, K., Katsumi, A., Kakeno, M., Matsui, T., Ye F.,Sato, K., Murase, K., Sugiyama,e I., Kimura, K., Mizoguchi, A., Matsuda, M., Ginsberg, MH., Collard, JG., and Kaibuchi, K. Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J. Cell. Biol. 199(2):331-345. (2012)
29. Kato, K., Yazawa, T., Taki, K., Mori, K., Wang, S., Nishioka, T., Hamaguchi, T., Itoh, T.,Takenawa, T., Kataoka, C., Matsuura, Y., Amano, M., Murohara, T., and Kaibuchi, K. The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration. Mol Biol Cell. 23(13):2593-2604. (2012)
30. Kuroda, K., Yamada, S., Tanaka, M., Iizuka, M., Yano, H., Mori, D., Tsuboi, D., Nishioka,T., Namba, T., Iizuka, Y., Kubota, S., Nagai, T., Ibi, D., Wang, R., Enomoto, A., Isotani-Sakakibara, M., Asai, N., Kimura, K., Kiyonari, H., Abe, T., Mizoguchi, A., Sokabe, M., Takahashi, M., Yamada, K., and Kaibuchi, K. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet. 20(23):4666-4683. (2011)
31. Sato, K., Watanabe, T., Wang, S., Kakeno, M.,Matsuzawa, K., Matsui,T., Yokoi,K., Murase, K., Sugiyama,I., Ozawa,M., and Kaibuchi, K. Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell. 22(17):3103-3119. (2011)
32. Nakamuta, S., Funahashi, Y., Namba, T., Arimura, N., Picciotto, MR., Tokumitsu, H., Soderling, TR., Sakakibara, A., Miyata, T., Kamiguchi, H., and Kaibuchi, K. Local Application of Neurotrophins Specifies Axons Through Inositol 1,4,5-Trisphosphate, Calcium, and Ca2+/Calmodulin-Dependent Protein Kinases. Science Signaling. ra76. (2011)
33. Arimura, N., Kimura, T., Nakamuta, S., Taya, S., Funahashi, Y., Hattori, A., Shimada, A., Menager, C., Kawabata, S., Fujii, K., Iwamatsu, A., Segal, R. A., Fukuda, M., and Kaibuchi, K. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell. 16 (5), 675-686. (2009)
34. Watanabe, T., Noritake, J., Kakeno, M., Matsui, T., Harada, T., Wang, S., Itoh, N., Sato, K., Matsuzawa, K., Iwamatsu, A., Galjart, N., and Kaibuchi, K. Phosphorylation of CLASP2 by GSK-3β regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci. 122(16):2969-2979. (2009)
35. Nakayama, M., Goto, T. M., Sugimoto, M., Nishimura, T., Shinagawa, T., Ohno, S., Amano, M., and Kaibuchi, K. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell. 14(2), 205-215. (2008)
36. Arimura, N., and Kaibuchi, K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci. 8, 194-205. (2007)
37. Taya, S., Shinoda, T., Tsuboi, D., Asaki, J., Nagai, K., Hikita, T., Kuroda, S., Kuroda, K., Shimizu, M., Hirotsune, S., Iwamatsu, A., and Kaibuchi, K. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci. 27(1):15-26. (2007)
38. Shinoda, T., Taya, S., Tsuboi, D., Hikita, T., Matsuzawa, R., Kuroda, S., Iwamatsu, A., and Kaibuchi, K. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci. 27(1):4-14. (2007)
39. Nishimura, T., and Kaibuchi, K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell. 13(1):15-28 . (2007)
40. Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., and Kaibuchi, K. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell. 120, 137-149. (2005)
41. Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y., Ohno, S., Hoshino, M., and Kaibuchi, K. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol. 7(3):270-277. (2005)
42. Arimura, N., Ménager, C., Kawano, Y., Yoshimura, T., Kawabata, S., Hattori, A., Fukata, Y., Amano, M., Goshima, Y., Inagaki, M., Morone, N., Usukura, J., and Kaibuchi, K. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol. 25(22):9973-9984. (2005)
43. Watanabe, T., Wang, S., Noritake, J., Sato, K., Fukata, M., Takefuji, M., Nakagawa, M., Izumi, N., Akiyama, T., and Kaibuchi, K. Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell. 7(6):871-883. (2004)
44. Nishimura, T., Kato, K., Yamaguchi, T., Fukata, Y., Ohno, S., and Kaibuchi, K. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nat Cell Biol. 6(4):328-334. (2004)
45. Nishimura, T., Fukata, Y., Kato, K., Yamaguchi, T., Matsuura, Y., Kamiguchi, H., and Kaibuchi, K. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol. 5(9):819-826. (2003)
46. Fukata, M., Watanabe, T., Noritake, J., Nakagawa, M., Yamaga, M., Kuroda, S., Matsuura, Y., Iwamatsu, A., Perez, F., and Kaibuchi, K. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell. 109, 873-885. (2002)
47. Fukata, Y., Itoh, TJ., Kimura, T., Ménager, C., Nishimura, T., Shiromizu, T., Watanabe, H., Inagaki, N., Iwamatsu, A., Hotani, H., and Kaibuchi, K. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol. 4(8):583-591. (2002)
48. Inagaki, N., Chihara, K., Arimura, N., Menager, C., Kawano, Y., Matsuo, N., Nishimura, T., Amano, M., and Kaibuchi, K. CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4, 781-782. (2001)
49. Kaibuchi, K., Kuroda, S., Amano, M. Regulation of cytoskeletons and cell adhesionsby the Rho family GTPases in mammalian cells. Annu Rev Biochem. 68, 459-486. (1999)
50. Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science. 271(5249):648-650. (1996)
51. Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 273, 245-248. (1996)
52. Matsui, T., Amano, M., Yamamoto, T., Chihara, K., Nakafuku, M., Ito, M., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15(9):2208-2216. (1996)
2. Lin, YH., Yamahashi, Y., Kuroda, K., Faruk, MO., Zhang, X., Yamada, K., Yamanaka, A., Nagai, T., Kaibuchi, K. Accumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. Neurochem Int. 143, 104935. (2021)
3. Chowdhury, MIH., Nishioka, T., Mishima, N., Ohtsuka, T., Kaibuchi, K., and Tsuboi, D. Prickle2 and Igsf9b coordinately regulate the cytoarchitecture of the axon initial segment. Cell Struct Funct. 45(2):143-154. (2020)
4. Funahashi, Y., Watanabe, T., and Kaibuchi, K. Advances in defining signaling networks for the establishment of neuronal polarity. Curr Opin Cell Biol. 63, 76-87. (2020)
5. Funahashi, Y., Ariza, A., Emi, R., Xu, Y., Shan, W., Suzuki, K., Kozawa, S., Ahammad, RU., Wu, M., Takano, T., Yura, Y., Kuroda, K., Nagai, T., Amano, M., Yamada, K., and Kaibuchi, K. Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors. Cell Rep. 29, 10, 3235-3252. (2019)
6. Zhang, X., Nagai, T., Ahammad, RU., Kuroda, K., Nakamuta, S., Nakano, T., Yukinawa, N., Funahashi, Y., Yamahashi, Y., Amano, M., Yoshimoto, J., Yamada, K., Kaibuchi, K. Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons. Neurochem Int. 122, 8-18. (2019)
7. Takano, T., Funahashi, Y., and Kaibuchi, K. Neuronal Polarity: Positive and Negative Feedback Signals. Front Cell Dev Biol. 7, 69. (2019)
8. Nishioka, T., Amano, M., Funahashi, Y., Tsuboi, D., Yamahashi, Y., and Kaibuchi, K. In Vivo Identification of Protein Kinase Substrates by Kinase-Oriented Substrate Screening (KIOSS). Curr Protoc Chem Biol. 11, 1, e60. (2019)
9. Amano, M., Nishioka, T., Tsuboi, D., Kuroda, K., Funahashi, Y., Yamahashi, Y., and Kaibuchi, K. Comprehensive analysis of kinase-oriented phospho-signalling pathways. J Biochem. 165, 4, 301-307. (2019)
10. Takano, T., Wu, M., Nakamuta, S., Honda, N., Ishizawa, N., Namba, T., Watanabe, T., Xu, C., Hamaguchi, T., Yura, Y., Amano, M., Hahn, K., and Kaibuchi, K. Discovery of Long-Range Inhibitory Signaling to Ensure Single Axon Formation. Nat commun. 8(1):33. (2017)
11. Nagai, T., Yoshimoto, J., Kannon, T., Kuroda, K., and Kaibuchi, K. Phosphorylation signals in striatal medium spiny neurons. Trend Pharmacol Sci. 37(10):858-71. (2016)
12. Nagai, T., Nakamuta, S., Kuroda, K., Nakauchi, S., Nishioka, T., Takano, T., Zhang, X., Tsuboi, D., Funahashi, Y., Nakano, T., Yoshimoto, J., Kobayashi, K., Uchigashima, M., Watanabe, M., Miura, M., Nishi, A., Kobayashi, K., Yamada, K., Amano, M., and Kaibuchi, K. Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo. Neuron. 89(3):550-565. (2016)
13. Matsuzawa, K., Akita, H., Watanabe, T., Kakeno, M., Matsui, T., Wang, S., and Kaibuchi, K. PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions. Mol Biol Cell. 27(9):1511-1523. (2016)
14. Amano, M., Hamaguchi, T., Shohag, MH., Kozawa, K., Kato, K., Zhang, X., Yura, Y., Matsuura, Y., Kataoka, C.,Nishioka, T., and Kaibuchi, K. Kinase-interacting substrate screening is a novel method to identify kinase substrates. J Cell Biol. 209(6), 895-912. (2015)
15. Tsuboi, D., Kuroda, K., Tanaka, M., Namba, T., Iizuka, Y., Taya, S., Shinoda, T., Hikita, T., Muraoka, S., Iizuka, M.,Nimura, A., Mizoguchi, A., Shiina, N., Sokabe, M., Okano, H., Mikoshiba, K., and Kaibuchi, K. Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosci. 18(5), 698-707. (2015)
16. Namba, T., Funahashi, Y., Nakamuta, S., Xu, C., Takano, T., and Kaibuchi, K. Extracellular and Intracellular Signaling for Neuronal Polarity. Physiol Rev. 95(3), 995-1024. (2015)
17. Xu,C., Funahashi, Y., Watanabe, T., Takano,T., Nakamuta, S., Namba, T., and Kaibuchi, K. Radial glial cell-neuron interaction directs axon formation at the opposite side of the neuron from the contact site. J Neurosci. 35(43):14517-14532. (2015)
18. Watanabe, T., Kakeno, M., Matsui, T., Sugiyama, I., Arimura, N., Matsuzawa, K., Shirahige, A., Ishidate, F., Nishioka, T., Taya, S., Hoshino, M., and Kaibuchi, K. TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation. J Cell Biol. 210(5):737-751. (2015)
19. Matsui, T., Watanabe, T., Matsuzawa, K., Kakeno, M., Okumura, N., Sugiyama, I., Itoh,N., and Kaibuchi, K. PAR3 and aPKC regulate Golgi organization through CLASP2 phosphorylation to generate cell polarity. Mol Biol Cell. 26(4):751-761. (2015)
20. Takano, T., Xu, C., Funahashi, Y., Namba, T., and Kaibuchi, K. Neuronal polarization. Development. 142(12):2088-2093. (2015)
21. Shohag, MH., Nishioka, T., Ahammad, RU., Nakamuta, S., Yura, Y., Hamaguchi, T, Kaibuchi, K., and Amano, M. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters. Cell Struct Funct. 40(2):95-104. (2015)
22. Hamaguchi, T., Nakamuta, S., Funahashi, Y., Takano, T., Nishioka, T., Hasanuzzaman, SM., Yura, Y., Kaibuchi, K., and Amano, M. In vivo Screening for Substrates of Protein Kinase A using a combination of proteomic approaches and pharmacological modulation of kinase activity. Cell Struct Funct. 40(1):1-12. (2015)
23. Namba, T., Kibe, Y., Funahashi, Y., Nakamuta, S., Takano, T., Ueno, T., Shimada, A., Kozawa, S., Okamoto, M., Shimoda, Y., Oda, K., Wada, Y., Masuda, T., Sakakibara, A., Igarashi, M., Miyata, T., Faivre-Sarrailh, C., Takeuchi, K., and Kaibuchi, K. Pioneering axons regulate neuronal polarization in the developing cerebral cortex. Neuron. 81, 814-829. (2014)
24. Funahashi, Y., Namba, T., Nakamuta, S., and Kaibuchi, K. Neuronal polarization in vivo: Growing in a complex environment. Neuronal polarization in vivo: Growing in a complex environment. Curr Opin Neurobiol. 27:215-223. (2014)
25. Kakeno, M., Matsuzawa, K., Matsui, T., Akita, H., Sugiyama, I., Ishidate, F., Nakano, A., Takashima, S., Goto, H., Inagaki, M., Kaibuchi. K., and Watanabe, T. Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment. Cell Struct Funct. 9(1):45-59. (2014)
26. Funahashi, Y., Namba, T., Fujisue, S., Itoh, N., Nakamuta, S., Kato, K., Shimada, A., Xu, C., Shan, W., Nishioka, T., and Kaibuchi, K. ERK2-mediated phosphorylation of Par3 regulates neuronal polarization. J Neurosci. 33, 13270-13285. (2013)
27. Nakayama, M., Nakayama, A., van Lessen, M., Yamamoto, H., Hoffmann, S., Drexler, HC., Itoh, N., Hirose, T., Breier, G., Vestweber, D., Cooper, JA., Ohno, S., Kaibuchi, K., and Adams, RH. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat Cell Biol. 15(3):249-260. (2013)
28. Wang, S., Watanabe, T., Matsuzawa, K., Katsumi, A., Kakeno, M., Matsui, T., Ye F.,Sato, K., Murase, K., Sugiyama,e I., Kimura, K., Mizoguchi, A., Matsuda, M., Ginsberg, MH., Collard, JG., and Kaibuchi, K. Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J. Cell. Biol. 199(2):331-345. (2012)
29. Kato, K., Yazawa, T., Taki, K., Mori, K., Wang, S., Nishioka, T., Hamaguchi, T., Itoh, T.,Takenawa, T., Kataoka, C., Matsuura, Y., Amano, M., Murohara, T., and Kaibuchi, K. The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration. Mol Biol Cell. 23(13):2593-2604. (2012)
30. Kuroda, K., Yamada, S., Tanaka, M., Iizuka, M., Yano, H., Mori, D., Tsuboi, D., Nishioka,T., Namba, T., Iizuka, Y., Kubota, S., Nagai, T., Ibi, D., Wang, R., Enomoto, A., Isotani-Sakakibara, M., Asai, N., Kimura, K., Kiyonari, H., Abe, T., Mizoguchi, A., Sokabe, M., Takahashi, M., Yamada, K., and Kaibuchi, K. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet. 20(23):4666-4683. (2011)
31. Sato, K., Watanabe, T., Wang, S., Kakeno, M.,Matsuzawa, K., Matsui,T., Yokoi,K., Murase, K., Sugiyama,I., Ozawa,M., and Kaibuchi, K. Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell. 22(17):3103-3119. (2011)
32. Nakamuta, S., Funahashi, Y., Namba, T., Arimura, N., Picciotto, MR., Tokumitsu, H., Soderling, TR., Sakakibara, A., Miyata, T., Kamiguchi, H., and Kaibuchi, K. Local Application of Neurotrophins Specifies Axons Through Inositol 1,4,5-Trisphosphate, Calcium, and Ca2+/Calmodulin-Dependent Protein Kinases. Science Signaling. ra76. (2011)
33. Arimura, N., Kimura, T., Nakamuta, S., Taya, S., Funahashi, Y., Hattori, A., Shimada, A., Menager, C., Kawabata, S., Fujii, K., Iwamatsu, A., Segal, R. A., Fukuda, M., and Kaibuchi, K. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell. 16 (5), 675-686. (2009)
34. Watanabe, T., Noritake, J., Kakeno, M., Matsui, T., Harada, T., Wang, S., Itoh, N., Sato, K., Matsuzawa, K., Iwamatsu, A., Galjart, N., and Kaibuchi, K. Phosphorylation of CLASP2 by GSK-3β regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci. 122(16):2969-2979. (2009)
35. Nakayama, M., Goto, T. M., Sugimoto, M., Nishimura, T., Shinagawa, T., Ohno, S., Amano, M., and Kaibuchi, K. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell. 14(2), 205-215. (2008)
36. Arimura, N., and Kaibuchi, K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci. 8, 194-205. (2007)
37. Taya, S., Shinoda, T., Tsuboi, D., Asaki, J., Nagai, K., Hikita, T., Kuroda, S., Kuroda, K., Shimizu, M., Hirotsune, S., Iwamatsu, A., and Kaibuchi, K. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci. 27(1):15-26. (2007)
38. Shinoda, T., Taya, S., Tsuboi, D., Hikita, T., Matsuzawa, R., Kuroda, S., Iwamatsu, A., and Kaibuchi, K. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci. 27(1):4-14. (2007)
39. Nishimura, T., and Kaibuchi, K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell. 13(1):15-28 . (2007)
40. Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., and Kaibuchi, K. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell. 120, 137-149. (2005)
41. Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y., Ohno, S., Hoshino, M., and Kaibuchi, K. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol. 7(3):270-277. (2005)
42. Arimura, N., Ménager, C., Kawano, Y., Yoshimura, T., Kawabata, S., Hattori, A., Fukata, Y., Amano, M., Goshima, Y., Inagaki, M., Morone, N., Usukura, J., and Kaibuchi, K. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol. 25(22):9973-9984. (2005)
43. Watanabe, T., Wang, S., Noritake, J., Sato, K., Fukata, M., Takefuji, M., Nakagawa, M., Izumi, N., Akiyama, T., and Kaibuchi, K. Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell. 7(6):871-883. (2004)
44. Nishimura, T., Kato, K., Yamaguchi, T., Fukata, Y., Ohno, S., and Kaibuchi, K. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nat Cell Biol. 6(4):328-334. (2004)
45. Nishimura, T., Fukata, Y., Kato, K., Yamaguchi, T., Matsuura, Y., Kamiguchi, H., and Kaibuchi, K. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol. 5(9):819-826. (2003)
46. Fukata, M., Watanabe, T., Noritake, J., Nakagawa, M., Yamaga, M., Kuroda, S., Matsuura, Y., Iwamatsu, A., Perez, F., and Kaibuchi, K. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell. 109, 873-885. (2002)
47. Fukata, Y., Itoh, TJ., Kimura, T., Ménager, C., Nishimura, T., Shiromizu, T., Watanabe, H., Inagaki, N., Iwamatsu, A., Hotani, H., and Kaibuchi, K. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol. 4(8):583-591. (2002)
48. Inagaki, N., Chihara, K., Arimura, N., Menager, C., Kawano, Y., Matsuo, N., Nishimura, T., Amano, M., and Kaibuchi, K. CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4, 781-782. (2001)
49. Kaibuchi, K., Kuroda, S., Amano, M. Regulation of cytoskeletons and cell adhesionsby the Rho family GTPases in mammalian cells. Annu Rev Biochem. 68, 459-486. (1999)
50. Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science. 271(5249):648-650. (1996)
51. Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 273, 245-248. (1996)
52. Matsui, T., Amano, M., Yamamoto, T., Chihara, K., Nakafuku, M., Ito, M., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15(9):2208-2216. (1996)