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  2. Tomoki Nishioka

Tomoki Nishioka

  (西岡 朋生)

Profile Information

Affiliation
Institute for Comprehensive Medical Science, Fujita Health University
Degree
博士（理学）
researchmap Member ID
5000090739

Research Interests

 4

Research Areas

 1

Papers

 61
  • Yasuhiro Funahashi, Rijwan Uddin Ahammad, Xinjian Zhang, Emran Hossen, Masahiro Kawatani, Shinichi Nakamuta, Akira Yoshimi, Minhua Wu, Huanhuan Wang, Mengya Wu, Xu Li, Md Omar Faruk, Md Hasanuzzaman Shohag, You-Hsin Lin, Daisuke Tsuboi, Tomoki Nishioka, Keisuke Kuroda, Mutsuki Amano, Yukihiko Noda, Kiyofumi Yamada, Kenji Sakimura, Taku Nagai, Takayuki Yamashita, Shigeo Uchino, Kozo Kaibuchi
    Science signaling, 17(853) eado9852, Sep 10, 2024  
    Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.
  • Takayuki Kannon, Satoshi Murashige, Tomoki Nishioka, Mutsuki Amano, Yasuhiro Funahashi, Daisuke Tsuboi, Yukie Yamahashi, Taku Nagai, Kozo Kaibuchi, Junichiro Yoshimoto
    Frontiers in Molecular Neuroscience, 17, Apr 2, 2024  
    Protein phosphorylation, a key regulator of cellular processes, plays a central role in brain function and is implicated in neurological disorders. Information on protein phosphorylation is expected to be a clue for understanding various neuropsychiatric disorders and developing therapeutic strategies. Nonetheless, existing databases lack a specific focus on phosphorylation events in the brain, which are crucial for investigating the downstream pathway regulated by neurotransmitters. To overcome the gap, we have developed a web-based database named “Kinase-Associated Neural PHOspho-Signaling (KANPHOS).” This paper presents the design concept, detailed features, and a series of improvements for KANPHOS. KANPHOS is designed to support data-driven research by fulfilling three key objectives: (1) enabling the search for protein kinases and their substrates related to extracellular signals or diseases; (2) facilitating a consolidated search for information encompassing phosphorylated substrate genes, proteins, mutant mice, diseases, and more; and (3) offering integrated functionalities to support pathway and network analysis. KANPHOS is also equipped with API functionality to interact with external databases and analysis tools, enhancing its utility in data-driven investigations. Those key features represent a critical step toward unraveling the complex landscape of protein phosphorylation in the brain, with implications for elucidating the molecular mechanisms underlying neurological disorders. KANPHOS is freely accessible to all researchers at https://kanphos.jp.
  • Daisuke Tsuboi, Takeshi Otsuka, Takushi Shimomura, Md Omar Faruk, Yukie Yamahashi, Mutsuki Amano, Yasuhiro Funahashi, Keisuke Kuroda, Tomoki Nishioka, Kenta Kobayashi, Hiromi Sano, Taku Nagai, Kiyofumi Yamada, Anastasios V Tzingounis, Atsushi Nambu, Yoshihiro Kubo, Yasuo Kawaguchi, Kozo Kaibuchi
    Cell reports, 40(10) 111309-111309, Sep 6, 2022  
    Dysfunctional dopamine signaling is implicated in various neuropsychological disorders. Previously, we reported that dopamine increases D1 receptor (D1R)-expressing medium spiny neuron (MSN) excitability and firing rates in the nucleus accumbens (NAc) via the PKA/Rap1/ERK pathway to promote reward behavior. Here, the results show that the D1R agonist, SKF81297, inhibits KCNQ-mediated currents and increases D1R-MSN firing rates in murine NAc slices, which is abolished by ERK inhibition. In vitro ERK phosphorylates KCNQ2 at Ser414 and Ser476; in vivo, KCNQ2 is phosphorylated downstream of dopamine signaling in NAc slices. Conditional deletion of Kcnq2 in D1R-MSNs reduces the inhibitory effect of SKF81297 on KCNQ channel activity, while enhancing neuronal excitability and cocaine-induced reward behavior. These effects are restored by wild-type, but not phospho-deficient KCNQ2. Hence, D1R-ERK signaling controls MSN excitability via KCNQ2 phosphorylation to regulate reward behavior, making KCNQ2 a potential therapeutical target for psychiatric diseases with a dysfunctional reward circuit.
  • Tomoo Owa, Ryo Shiraishi, Toma Adachi, Satoshi Miyashita, Kentaro Ichijo, Tomoki Nishioka, Shinichiro Taya, Kozo Kaibuchi, Mikio Hoshino
    Aug 17, 2022  
    Abstract Granule cell progenitors (GCPs) and granule cells (GCs) in the cerebellum are excellent models for studying the differentiation of neural progenitors into neurons. Although gradual degradation of ATOH1 protein in GCPs leads to their differentiation into GCs, the underlying regulatory mechanism is unclear. We show that a homeodomain-less isoform of MEIS1 (MEIS1-HdL) regulates ATOH1 degradation and GCP differentiation in a transcriptional regulation-independent manner. BMP signaling phosphorylates Ser328 of ATOH1 via ERK. CUL3 was identified as an E3-ligase that polyubiquitinates Ser328 phosphorylated ATOH1, leading to ATOH1 degradation. MEIS1-HdL and full-length MEIS1 form a trimeric complex with CUL3 and COP9 signalosome that inhibits ATOH1 ubiquitination and degradation. MEIS1-HdL is exclusively expressed in GCPs and suppresses ATOH1 degradation and GCP differentiation into GCs, despite high BMP signaling activities in the cells. Our study provides insight into the precise regulatory machinery of the degradation of the pivotal protein ATOH1 and differentiation of neural progenitors.
  • Tomoo Owa, Ryo Shiraishi, Toma Adachi, Satoshi Miyashita, Kentaro Ichijo, Tomoki Nishioka, Shinichiro Taya, Kozo Kaibuchi, Mikio Hoshino
    Aug 17, 2022  
    Abstract Granule cell progenitors (GCPs) and granule cells (GCs) in the cerebellum are excellent models for studying the differentiation of neural progenitors into neurons. Although gradual degradation of ATOH1 protein in GCPs leads to their differentiation into GCs, the underlying regulatory mechanism is unclear. We show that a homeodomain-less isoform of MEIS1 (MEIS1-HdL) regulates ATOH1 degradation and GCP differentiation in a transcriptional regulation-independent manner. BMP signaling phosphorylates Ser328 of ATOH1 via ERK. CUL3 was identified as an E3-ligase that polyubiquitinates Ser328 phosphorylated ATOH1, leading to ATOH1 degradation. MEIS1-HdL and full-length MEIS1 form a trimeric complex with CUL3 and COP9 signalosome that inhibits ATOH1 ubiquitination and degradation. MEIS1-HdL is exclusively expressed in GCPs and suppresses ATOH1 degradation and GCP differentiation into GCs, despite high BMP signaling activities in the cells. Our study provides insight into the precise regulatory machinery of the degradation of the pivotal protein ATOH1 and differentiation of neural progenitors.
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Misc.

 14
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Research Projects

 5
  • Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Apr, 2017 - Mar, 2021
    Kaibuchi Kozo
  • Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Apr, 2013 - Mar, 2016
    Kaibuchi Kozo
  • Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Apr, 2010 - Mar, 2016
    Kimura Minoru, Tanji Jun, Takada Masahiko, Nakamura Katsuki, Ohtsuka Toshihisa, Aoki Shigeki, Takao Hidemasa, Shimoji Keigo, Goto Masami, Yoshiura Takashi, Nakata Yasuhiro, Abe Osamu, Masumoto Tomohiko, Tokumaru Aya, Matsumura Akira, Kirino Eiji, Terada Hitoshi, Sato Noriko, Kasai Kiyoto, Hashimoto Ryota, Niwa Shin-ichi, Kato Tadafumi, Suzuki Michio, Shuji Iritani, Nemoto Kiyotaka, Tomita Hiroaki, Murayama Shigeo, Akatsu Hiroyasu, Takao Masaki, Saito Yuko, Bito Haruhiko, Yoshimura Yumiko, Matsuzaki Masanori, Furuta Toshiaki, Okado Haruo, Saito Izumu, Kaibuchi Kozo, Hasegawa Masato, Aiba Atsu, Shiina Nobuyuki, Igarashi Michihiro, Tomoki Nishioka, Watanabe Masahiko, Koike Masato, Sakagami Hiroyuki, Shigemoto Ryuichi, Fukazawa Yugo, Sakimura Kenji, Mori Hisashi, Mishina Masayoshi, Kobayashi Kazuto, Yanagawa Yuchio, Uemura Tadashi, Ishihara Takeshi, Nose Akinao, Iino Yuichi, Miyakawa Tsuyoshi, Takao Keizo, Mushiake Hajime, Katayama Norihiro, Tanaka Tetsu, Inoue Kazuhide, Okabe Shigeo, Kano Masanobu, Fujiyama Fumino, Isa Tadashi, Kageyama Ryoichiro, Fujita Ichiro, Yoshida Akira, Nishikawa Toru, Nukina Nobuyuki, Fukai Tomoki, Iwatsubo Takeshi, Yamamori Tetsuo, Okazawa Hitoshi, Tanaka Keiji, Kakigi Ryusuke, Tsuda Ichiro, Kitazawa Shigeru, Doya Kenji, Takahashi Ryosuke, Ikenaka Kazuhiro, Sobue Gen, Hasegawa Toshikazu, Ota Jun, Saitoe Minoru, Kadomatsu Kenji, Kida Satoshi, Manabe Toshiya, Tomita Taisuke, Iwata Atsushi, Murakami Ikuya, Tsutsui Ken-ichiro, Hanakawa Takashi, Hirai Hirokazu, Mima Tatsuya, Isomura Yoshikazu, Samejima Kazuyuki, Hoshi Eiji, Miyata Mariko, Yuzaki Michisuke, Tanaka Masaki, Fukata Masaki, Suzuki Kyoko, Kuba Hiroshi, Masu Masayuki, Kinoshita Makoto, Sugihara Izumi, Shirane Michiko, Yamamoto Nobuhiko, Nishijo Hisao, Nambu Atsushi, Takumi Toru, Yamashita Toshihide, Sakurai Takeshi, Tamamaki Nobuaki, Hata Yoshio, Harada Akihiro, Ozaki Norio, Sakai Katsuyuki, Kubo Yoshihiro, Nakazawa Takanobu, Tanaka Kenji, Takei Nobuyuki, Hitoshi Seiji, Takahiroa. Kato, Kato Fusao, Shirao Tomoaki, Taira Masato, Okano Hideyuki, Sekino Yuko, Okamoto Yasumasa, KOMATSU Hidehiko, Miyata Takaki, Takahashi Yoshiko, Nishida Shinya, Tominaga Makoto
  • Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, 2008 - 2012
    KAIBUCHI Kozo, AMANO Mutsuki, WATANABE Takashi, MORI Daisuke, NISHIOKA Tomoki, TSUBOI Daisuke, ARIMURA Nariko
  • Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, 2005 - 2009
    KAIBUCHI Kozo, NARIKO Arimura, DAISUKE Mori, TOMOKI Nishioka

Other

 1
  • 質量分析装置を用いた組織、細胞レベルの網羅的in vivoリン酸化シグナルネットワーク解析技術（KIOSS: Nishioka et.al., Curr Protoc Chem Biol. 2019 Mar;11(1):e60. doi: 10.1002/cpch.60.) ＊本研究シーズに関する産学共同研究の問い合わせは藤田医科大学産学連携推進セン ター（fuji-san@fujita-hu.ac.jp）まで
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