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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

 60
  • 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.
  • Md Omar Faruk, Daisuke Tsuboi, Yukie Yamahashi, Yasuhiro Funahashi, You-Hsin Lin, Rijwan Uddin Ahammad, Emran Hossen, Mutsuki Amano, Tomoki Nishioka, Anastasios V Tzingounis, Kiyofumi Yamada, Taku Nagai, Kozo Kaibuchi
    Journal of neurochemistry, 160(3) 325-341, Feb, 2022  
    The nucleus accumbens (NAc) plays critical roles in emotional behaviors, including aversive learning. Aversive stimuli such as an electric foot shock increase acetylcholine (ACh) in the NAc, and muscarinic signaling appears to increase neuronal excitability and aversive learning. Muscarinic signaling inhibits the voltage-dependent potassium KCNQ current which regulates neuronal excitability, but the regulatory mechanism has not been fully elucidated. Phosphorylation of KCNQ2 at threonine 217 (T217) and its inhibitory effect on channel activity were predicted. However, whether and how muscarinic signaling phosphorylates KCNQ2 in vivo remains unclear. Here, we found that PKC directly phosphorylated KCNQ2 at T217 in vitro. Carbachol and a muscarinic M1 receptor (M1R) agonist facilitated KCNQ2 phosphorylation at T217 in NAc/striatum slices in a PKC-dependent manner. Systemic administration of the cholinesterase inhibitor donepezil, which is commonly used to treat dementia, and electric foot shock to mice induced the phosphorylation of KCNQ2 at T217 in the NAc, whereas phosphorylation was suppressed by an M1R antagonist. Conditional deletion of Kcnq2 in the NAc enhanced electric foot shock induced aversive learning. Our findings indicate that muscarinic signaling induces the phosphorylation of KCNQ2 at T217 via PKC activation for aversive learning.
  • Funahashi Yasuhiro, Ahammad Rijwan Uddin, Zhang Xinjian, Emran Hossen, Faruk Md. Omar, Wang Huanhuan, Wu Minhua, Xu Yifan, Tsuboi Daisuke, Nishioka Tomoki, Kuroda Keisuke, Amano Mutsuki, Sakimura Kenji, Uchino Shigeo, Yamada Kiyofumi, Nagai Taku, Kaibuchi Kozo
    Proceedings for Annual Meeting of The Japanese Pharmacological Society, 96 2-B-P-109, 2022  
    Glutamate induces Ca2+ influx in neurons through NMDA receptors (NMDARs) and activates Ca2+-dependent protein kinases, including CaMKII, which play critical roles in synaptic plasticity and learning. However, how these kinases regulate synaptic plasticity and learning remains largely unknown. Here, we performed phosphoproteomics and identified 160 proteins including ArhGEF2 whose phosphorylation were promoted by NMDA. CaMKII phosphorylated ArhGEF2 and stimulated its RhoGEF activity. Aversive stimuli induced CaMKII-mediated ArhGEF2 phosphorylation and Rho-kinase/ROCK activation in the nucleus accumbens (NAc). Inhibition of Rho-kinase in the NAc attenuated aversive learning. We also screened Rho-kinase substrates and identified 221 proteins including Shank3 which links actin filaments with NMDARs and AMPA receptors via Dlgap3. The Rho-kinase-mediated phosphorylation of Shank3 increased its interaction with Dlgap3. Manipulation of Shank3 in the NAc regulated dendritic spine formation and aversive learning in a phosphorylation-dependent manner. These results demonstrate that NMDA activates the CaMKII-ArhGEF2-Rho-kinase pathway to induce Shank3 phosphorylation for aversive learning.
  • Rijwan Uddin Ahammad, Tomoki Nishioka, Junichiro Yoshimoto, Takayuki Kannon, Mutsuki Amano, Yasuhiro Funahashi, Daisuke Tsuboi, Md. Omar Faruk, Yukie Yamahashi, Kiyofumi Yamada, Taku Nagai, Kozo Kaibuchi
    Cells, 11(1) 47-47, Dec 24, 2021  
    Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The “KANPHOS” (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways.
  • Nariko Arimura, Mako Okada, Shinichiro Taya, Ken-ichi Dewa, Akiko Tsuzuki, Hirotomo Uetake, Satoshi Miyashita, Koichi Hashizume, Kazumi Shimaoka, Saki Egusa, Tomoki Nishioka, Yuchio Yanagawa, Kazuhiro Yamakawa, Yukiko U. Inoue, Takayoshi Inoue, Kozo Kaibuchi, Mikio Hoshino
    Science Advances, 6(36) eaba1693-eaba1693, Sep, 2020  
    For normal neurogenesis and circuit formation, delamination of differentiating neurons from the proliferative zone must be precisely controlled; however, the regulatory mechanisms underlying cell attachment are poorly understood. Here, we show that Down syndrome cell adhesion molecule (DSCAM) controls neuronal delamination by local suppression of the RapGEF2–Rap1–N-cadherin cascade at the apical endfeet in the dorsal midbrain. <italic>Dscam</italic> transcripts were expressed in differentiating neurons, and DSCAM protein accumulated at the distal part of the apical endfeet. Cre-<italic>loxP</italic>–based neuronal labeling revealed that <italic>Dscam</italic> knockdown impaired endfeet detachment from ventricles. DSCAM associated with RapGEF2 to inactivate Rap1, whose activity is required for membrane localization of N-cadherin. Correspondingly, <italic>Dscam</italic> knockdown increased N-cadherin localization and ventricular attachment area at the endfeet. Furthermore, excessive endfeet attachment by <italic>Dscam</italic> knockdown was restored by co-knockdown of <italic>RapGEF2</italic> or <italic>N-cadherin</italic>. Our findings shed light on the molecular mechanism that regulates a critical step in early neuronal development.
  • Satoshi Miyashita, Tomoo Owa, Yusuke Seto, Mariko Yamashita, Shogo Aida, Tomoki Nishioka, Kozo Kaibuchi, Yoshiya Kawaguchi, Shinichiro Taya, Mikio Hoshino
    Mar 29, 2020  
    <title>Abstract</title>Here we report that CyclinD1 (CCND1) directly regulates both the proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates Ser309 of ATOH1, which inhibits additional phosphorylation at S328, consequently preventing Ser328 phosphorylation-dependent ATOH1 degradation. PROX1 downregulates Ccnd1 expression by histone-deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferation and immaturity of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which was suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.
  • Huan Sun, Tomoki Nishioka, Shun Hiramatsu, Shu Kondo, Mutsuki Amano, Kozo Kaibuchi, Toshiharu Ichinose, Hiromu Tanimoto
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(14) 2935-2942, Feb 24, 2020  Peer-reviewed
    In Drosophila, dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative conditioning increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of Dop1R2, Raf or MAPK expression in KCs selectively impairs LTM but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of Dop1R2 can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory.SIGNIFICANCE STATEMENTDopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in Drosophila This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization.
  • Md. Imrul Hasan Chowdhury, Tomoki Nishioka, Noriko Mishima, Toshihisa Ohtsuka, Kozo Kaibuchi, Daisuke Tsuboi
    Cell Structure and Function, 45(2) 143-154, 2020  
  • Mariko Kato Hayashi, Tomoki Nishioka, Hideo Shimizu, Kanako Takahashi, Wataru Kakegawa, Tetsuri Mikami, Yuri Hirayama, Schuichi Koizumi, Sachiko Yoshida, Michisuke Yuzaki, Markku Tammi, Yuko Sekino, Kozo Kaibuchi, Yukari Shigemoto-Mogami, Masato Yasui, Kaoru Sato
    Journal of neurochemistry, 150(3) 249-263, Aug, 2019  Peer-reviewed
    Hyaluronan is synthesized, secreted, and anchored by hyaluronan synthases (HAS) at the plasma membrane and comprises the backbone of perineuronal nets around neuronal soma and dendrites. However, the molecular targets of hyaluronan to regulate synaptic transmission in the central nervous system have not been fully identified. Here, we report that hyaluronan is a negative regulator of excitatory signals. At excitatory synapses, glutamate is removed by glutamate transporters to turn off the signal and prevent excitotoxicity. Hyaluronan synthesized by HAS supports the activity of glial glutamate transporter 1 (GLT1). GLT1 also retracted from cellular processes of cultured astrocytes after hyaluronidase treatment and hyaluronan synthesis inhibition. A serial knockout study showed that all three HAS subtypes recruit GLT1 to cellular processes. Furthermore, hyaluronidase treatment activated neurons in a dissociated rat hippocampal culture and caused neuronal damage due to excitotoxicity. Our findings reveal that hyaluronan helps to turn off excitatory signals by supporting glutamate clearance. Cover Image for this issue: doi: 10.1111/jnc.14516.
  • Yamaoka M, Terabayashi T, Nishioka T, Kaibuchi K, Ishikawa T, Ishizaki T, Kimura T
    Journal of pharmacological sciences, 140(3) 300-304, Jul, 2019  Peer-reviewed
  • Hiroshi Hanafusa, Takuya Yagi, Haruka Ikeda, Naoki Hisamoto, Tomoki Nishioka, Kozo Kaibuchi, Kyoko Shirakabe, Kunihiro Matsumoto
    Journal of cell science, 132(11), Jun 3, 2019  
    Ligand-induced activation of epidermal growth factor receptor (EGFR) initiates trafficking events that re-localize the receptor from the cell surface to intracellular endocytic compartments. EGFR-containing endosomes are transported to lysosomes for degradation by the dynein-dynactin motor protein complex. However, this cargo-dependent endosomal trafficking mechanism remains largely uncharacterized. Here, we show that GTP-bound Rab7 is phosphorylated on S72 by leucine-rich repeat kinase 1 (LRRK1) at the endosomal membrane. This phosphorylation promotes the interaction of Rab7 (herein referring to Rab7a) with its effector RILP, resulting in recruitment of the dynein-dynactin complex to Rab7-positive vesicles. This, in turn, facilitates the dynein-driven transport of EGFR-containing endosomes toward the perinuclear region. These findings reveal a mechanism regulating the cargo-specific trafficking of endosomes.
  • Nishioka T, Amano M, Funahashi Y, Tsuboi D, Yamahashi Y, Kaibuchi K
    Current protocols in chemical biology, 11(1) e60, Jan 7, 2019  
    Protein phosphorylation plays a critical role in the regulation of cellular function. Information on protein phosphorylation and the responsible kinases is important for understanding intracellular signaling. A method for in vivo screening of kinase substrates named KIOSS (kinase-oriented substrate screening) has been developed. This protocol provides a method that utilizes phosphoprotein-binding modules such as 14-3-3 protein, the pin1-WW domain, and the chek2-FHA domain as biological filters to successfully enrich phosphorylated proteins related to intracellular signaling rather than housekeeping and/or structural proteins. More than 1000 substrate candidates for PKA, PKC, MAPK, and Rho-kinase in HeLa cells, as well as phosphorylation downstream of D1R, NMDAR, adenosine A2a receptor, PKA, PKC, MAPK, and Rho-kinase in mouse brain slice cultures have been identified by this method. An online database named KANPHOS (Kinase-Associated Neural Phospho-Signaling) provides the phosphorylation signals identified by these studies, as well as those previously reported in the literature. © 2019 by John Wiley & Sons, Inc.
  • Kuroda Keisuke, Nagai Taku, Amano Mutsuki, Yoshimoto Junichiro, Kannon Takayuki, Nishioka Tomoki, Usui Shiro, Kaibuchi Kozo
    Proceedings for Annual Meeting of The Japanese Pharmacological Society, 92 1-P-132, 2019  
    <p>Protein phosphorylation is a major and essential post-translational modification in eukaryotic cells that plays a critical role in various cellular processes. While recent advances in mass spectrometry based proteomics allowed us to identify approximately 200,000 phosphorylation sites, it is not fully understood which sites are phosphorylated by a specific kinase and which extracellular stimuli regulate the protein phosphorylation via intracellular signaling cascades. Recently, we have developed an in vitro approach termed the kinase-interacting substrate screening (KISS) method and an in vivo approach termed kinase-oriented substrate screening (KIOSS) method. Using KIOSS method, we analyzed the phosphorylation signals downstream of dopamine in mouse striatal slices, and found that about 100 proteins including ion channels and transcription factors were phosphorylated probably by PKA or MAPK. Here, we present an on-line database system which provides the phosphorylation signals identified by our KISS and KIOSS methods as well as those previously reported in the literature. The database system and its web portal, named KANPHOS (Kinase-Associated PHOspho-Signaling), were built based on the Next Generation XooNIps. We also demonstrate how to retrieve proteins and pathways in striatal medium-sized spiny neurons modulated by extracellular dopaminergic stimulation.</p>
  • Ogino K, Yamada K, Nishioka T, Oda Y, Kaibuchi K, Hirata H
    Journal of Neuroscience, 39(45) 8988-8997, 2019  Peer-reviewed
  • Amano M, Nishioka T, Tsuboi D, Kuroda K, Funahashi Y, Yamahashi Y, Kaibuchi K
    Journal of biochemistry, 165(4) 301-307, Dec 24, 2018  
    Accumulating information on eukaryotic protein phosphorylation implies a large and complicated phospho-signalling network in various cellular processes. Although a large number of protein phosphorylation sites have been detected, their physiological consequences and the linkage between each phosphorylation site and the responsible protein kinase remain largely unexplored. To understand kinase-oriented phospho-signalling pathways, we have developed novel substrate screening technologies. In this review, we described the in vitro and in vivo screening methods named kinase-interacting substrate screening analysis and kinase-oriented substrate screening analysis, respectively.
  • Tomoo Owa, Shinichiro Taya, Satoshi Miyashita, Mariko Yamashita, Toma Adachi, Koyo Yamada, Miwa Yokoyama, Shogo Aida, Tomoki Nishioka, Yukiko U. Inoue, Ryo Goitsuka, Takuro Nakamura, Takayoshi Inoue, Kozo Kaibuchi, Mikio Hoshino
    Journal of Neuroscience, 38(5) 1277-1294, Jan 31, 2018  Peer-reviewed
  • Taku Nagai, Shinichi Nakamuta, Keisuke Kuroda, Sakura Nakauchi, Tomoki Nishioka, Tetsuya Takano, Xinjian Zhang, Daisuke Tsuboi, Yasuhiro Funahashi, Takashi Nakano, Junichiro Yoshimoto, Kenta Kobayashi, Motokazu Uchigashima, Masahiko Watanabe, Masami Miura, Akinori Nishi, Kazuto Kobayashi, Kiyofumi Yamada, Mutsuki Amano, Kozo Kaibuchi
    Neuron, 89(3) 550-65, Feb 3, 2016  Peer-reviewed
    Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1. Cocaine exposure activated Rap1 in the nucleus accumbens in mice. The expression of constitutively active PKA or Rap1 in accumbal D1R-expressing medium spiny neurons (D1R-MSNs) enhanced neuronal firing rates and behavioral responses to cocaine exposure through MAPK. Knockout of Rap1 in the accumbal D1R-MSNs was sufficient to decrease these phenotypes. These findings demonstrate a novel DA-PKA-Rap1-MAPK intracellular signaling mechanism in D1R-MSNs that increases neuronal excitability to enhance reward-related behaviors.
  • Nagai T, Nakamuta S, Kuroda K, Nakauchi S, Nishioka T, Takano T, Xinjian Zhang, Kenta Kobayashi K, Miura M, Nishi A, Kobayashi K, Yamada K, Amano M, Kaibuchi K
    Neuron, 89(3) 550-565, Feb, 2016  Peer-reviewed
  • Mami Yamaoka, Tomomi Ando, Takeshi Terabayashi, Mitsuhiro Okamoto, Masahiro Takei, Tomoki Nishioka, Kozo Kaibuchi, Kohichi Matsunaga, Ray Ishizaki, Tetsuro Izumi, Ichiro Niki, Toshimasa Ishizaki, Toshihide Kimura
    JOURNAL OF CELL SCIENCE, 129(3) 637-649, Feb, 2016  Peer-reviewed
  • Kyogo Kobayashi, Shunji Nakano, Mutsuki Amano, Daisuke Tsuboi, Tomoki Nishioka, Shingo Ikeda, Genta Yokoyama, Kozo Kaibuchi, Ikue Mori
    CELL REPORTS, 14(1) 11-21, Jan, 2016  Peer-reviewed
  • Yoshimitsu Yura, Mutsuki Amano, Mikito Takefuji, Tomohiro Bando, Kou Suzuki, Katsuhiro Kato, Tomonari Hamaguchi, Md. Hasanuzzaman Shohag, Tetsuya Takano, Yasuhiro Funahashi, Shinichi Nakamuta, Keisuke Kuroda, Tomoki Nishioka, Toyoaki Murohara, Kozo Kaibuchi
    CELL STRUCTURE AND FUNCTION, 41(2) 105-120, 2016  Peer-reviewed
  • Mutsuki Amano, Tomoki Nishioka, Yoshimitsu Yura, Kozo Kaibuchi
    Current Protocols in Cell Biology, 2016 14.16.1-12, 2016  Peer-reviewed
  • Natsumi Ageta-Ishihara, Maya Yamazaki, Kohtarou Konno, Hisako Nakayama, Manabu Abe, Kenji Hashimoto, Tomoki Nishioka, Kozo Kaibuchi, Satoko Hattori, Tsuyoshi Miyakawa, Kohichi Tanaka, Fathul Huda, Hirokazu Hirai, Kouichi Hashimoto, Masahiko Watanabe, Kenji Sakimura, Makoto Kinoshita
    NATURE COMMUNICATIONS, 6 10090, Dec, 2015  Peer-reviewed
  • Tomoki Nishioka, Md. Hasanuzzaman Shohag, Mutsuki Amano, Kozo Kaibuchi
    BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 1854(10) 1663-1666, Oct, 2015  Peer-reviewed
  • Nishioka T, Shohag MH, Amano M, Kaibuchi K
    Biochimica et biophysica acta, 1854(10 Pt B) 1663-1666, Oct, 2015  Peer-reviewed
  • Takashi Watanabe, Mai Kakeno, Toshinori Matsui, Ikuko Sugiyama, Nariko Arimura, Kenji Matsuzawa, Aya Shirahige, Fumiyoshi Ishidate, Tomoki Nishioka, Shinichiro Taya, Mikio Hoshino, Kozo Kaibuchi
    JOURNAL OF CELL BIOLOGY, 210(5) 737-751, Aug, 2015  Peer-reviewed
  • Taeko Kobayashi, Yumiko Iwamoto, Kazuhiro Takashima, Akihiro Isomura, Yoichi Kosodo, Koichi Kawakami, Tomoki Nishioka, Kozo Kaibuchi, Ryoichiro Kageyama
    FEBS JOURNAL, 282(13) 2475-2487, Jul, 2015  Peer-reviewed
  • Amano, M, Hamaguchi, T, Shohag, M. H, Kozawa, K, Kato, K, Zhang, X, Yura, Y, Matsuura, Y, Kataoka, C, Nishioka, T, Kaibuchi, K
    J Cell Biol, 209(6) 895-912-912, Jun 22, 2015  Peer-reviewed
    Protein kinases play pivotal roles in numerous cellular functions; however, the specific substrates of each protein kinase have not been fully elucidated. We have developed a novel method called kinase-interacting substrate screening (KISS). Using this method, 356 phosphorylation sites of 140 proteins were identified as candidate substrates for Rho-associated kinase (Rho-kinase/ROCK2), including known substrates. The KISS method was also applied to additional kinases, including PKA, MAPK1, CDK5, CaMK1, PAK7, PKN, LYN, and FYN, and a lot of candidate substrates and their phosphorylation sites were determined, most of which have not been reported previously. Among the candidate substrates for Rho-kinase, several functional clusters were identified, including the polarity-associated proteins, such as Scrib. We found that Scrib plays a crucial role in the regulation of subcellular contractility by assembling into a ternary complex with Rho-kinase and Shroom2 in a phosphorylation-dependent manner. We propose that the KISS method is a comprehensive and useful substrate screen for various kinases.
  • Mutsuki Amano, Tomonari Hamaguchi, Md. Hasanuzzaman Shohag, Kei Kozawa, Katsuhiro Kato, Xinjian Zhang, Yoshimitsu Yura, Yoshiharu Matsuura, Chikako Kataoka, Tomoki Nishioka, Kozo Kaibuchi
    JOURNAL OF CELL BIOLOGY, 209(6) 895-912, Jun, 2015  Peer-reviewed
  • Atsushi Kiyota, Shintaro Iwama, Yoshihisa Sugimura, Seiji Takeuchi, Hiroshi Takagi, Naoko Iwata, Kohtaro Nakashima, Haruyuki Suzuki, Tomoki Nishioka, Takuya Kato, Atsushi Enomoto, Hiroshi Arima, Kozo Kaibuchi, Yutaka Oiso
    ENDOCRINE JOURNAL, 62(2) 153-160, Feb, 2015  Peer-reviewed
  • Shin Kedashiro, Strahil Iv. Pastuhov, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi, Kunihiro Matsumoto, Hiroshi Hanafusa
    JOURNAL OF CELL SCIENCE, 128(4) 829-829, Feb, 2015  Peer-reviewed
  • Tomonari Hamaguchi, Shinichi Nakamuta, Yasuhiro Funahashi, Tetsuya Takano, Tomoki Nishioka, Md. Hasanuzzaman Shohag, Yoshimitsu Yura, Kozo Kaibuchi, Mutsuki Amano
    CELL STRUCTURE AND FUNCTION, 40(1) 1-12, 2015  Peer-reviewed
  • Shin Kedashiro, Strahil Iv. Pastuhov, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi, Kunihiro Matsumoto, Hiroshi Hanafusa
    JOURNAL OF CELL SCIENCE, 128(2) 385-396, Jan, 2015  Peer-reviewed
  • Md. Hasanuzzaman Shohag, Tomoki Nishioka, Rijwan Uddin Ahammad, Shinichi Nakamuta, Yoshimitsu Yura, Tomonari Hamaguchi, Kozo Kaibuchi, Mutsuki Amano
    CELL STRUCTURE AND FUNCTION, 40(2) 95-104, 2015  Peer-reviewed
  • Kei Hori, Taku Nagai, Wei Shan, Asami Sakamoto, Shinichiro Taya, Ryoya Hashimoto, Takashi Hayashi, Manabu Abe, Maya Yamazaki, Keiko Nakao, Tomoki Nishioka, Kenji Sakimura, Kiyofumi Yamada, Kozo Kaibuchi, Mikio Hoshino
    CELL REPORTS, 9(6) 2166-2179, Dec, 2014  Peer-reviewed
  • Haruko Ota, Takao Hikita, Masato Sawada, Tomoki Nishioka, Mami Matsumoto, Masayuki Komura, Akihisa Ohno, Yukiyo Kamiya, Takuya Miyamoto, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto
    NATURE COMMUNICATIONS, 5 4532, Jul, 2014  Peer-reviewed
  • Haruko Ota, Takao Hikita, Tomoki Nishioka, Mami Matsumoto, Jun Ito, Naoya Asai, Atsushi Enomoto, Masahide Takahashi, Kozo Kaibuchi, Kazuya Sobue, Kazunobu Sawamoto
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 442(1-2) 16-21, Dec, 2013  Peer-reviewed
  • Yasuhiro Funahashi, Takashi Namba, Shin Fujisue, Norimichi Itoh, Shinichi Nakamuta, Katsuhiro Kato, Akiko Shimada, Chundi Xu, Wei Shan, Tomoki Nishioka, Kozo Kaibuchi
    JOURNAL OF NEUROSCIENCE, 33(33) 13270-13285, Aug, 2013  Peer-reviewed
  • Katsuhiro Kato, Tsubasa Yazawa, Kentaro Taki, Kazutaka Mori, Shujie Wang, Tomoki Nishioka, Tomonari Hamaguchi, Toshiki Itoh, Tadaomi Takenawa, Chikako Kataoka, Yoshiharu Matsuura, Mutsuki Amano, Toyoaki Murohara, Kozo Kaibuchi
    MOLECULAR BIOLOGY OF THE CELL, 23(13) 2593-2604, Jul, 2012  Peer-reviewed
  • 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, Kaibuchi, K
    Mol Biol Cell, 23(13) 2593-2604-2604, May 18, 2012  Peer-reviewed
    Cell migration is essential for various physiological and pathological processes. Polarization in motile cells requires the coordination of several key signaling molecules, including RhoA small GTPases and phosphoinositides. Although RhoA participates in a front-rear polarization in migrating cells, little is known about the functional interaction between RhoA and lipid turnover. We find here that src-homology 2-containing inositol-5-phosphatase 2 (SHIP2) interacts with RhoA in a GTP-dependent manner. The association between SHIP2 and RhoA is observed in spreading and migrating U251 glioma cells. The depletion of SHIP2 attenuates cell polarization and migration, which is rescued by wild-type SHIP2 but not by a mutant defective in RhoA binding. In addition, the depletion of SHIP2 impairs the proper localization of phosphatidylinositol 3,4,5-trisphosphate, which is not restored by a mutant defective in RhoA binding. These results suggest that RhoA associates with SHIP2 to regulate cell polarization and migration.
  • Nishioka, T, Nakayama, M, Amano, M, Kaibuchi, K
    Cell Struct Funct, 37(1) 39-48, Jan 19, 2012  Peer-reviewed
    The small GTPase RhoA is a molecular switch in various extracellular signals. Rho-kinase/ROCK/ROK, a major effector of RhoA, regulates diverse cellular functions by phosphorylating cytoskeletal proteins, endocytic proteins, and polarity proteins. More than twenty Rho-kinase substrates have been reported, but the known substrates do not fully explain the Rho-kinase functions. Herein, we describe the comprehensive screening for Rho-kinase substrates by treating HeLa cells with Rho-kinase and phosphatase inhibitors. The cell lysates containing the phosphorylated substrates were then subjected to affinity chromatography using beads coated with 14-3-3 protein, which interacts with proteins containing phosphorylated serine or threonine residues, to enrich the phosphorylated proteins. The identities of the molecules and phosphorylation sites were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS) after tryptic digestion and phosphopeptide enrichment. The phosphorylated proteins whose phosphopeptide ion peaks were suppressed by treatment with the Rho-kinase inhibitor were regarded as candidate substrates. We identified 121 proteins as candidate substrates. We also iden
  • Tsuboi Daisuke, Amano Mutsuki, Nishioka Tomiki, Kaibuchi Kozo
    Abstracts for Annual Meeting of Japanese Proteomics Society, 2012 63-63, 2012  
  • Tomoki Nishioka, Masanori Nakayama, Mutsuki Amano, Kozo Kaibuchi
    CELL STRUCTURE AND FUNCTION, 37(1) 39-48, 2012  Peer-reviewed
  • Keisuke Kuroda, Shinnosuke Yamada, Motoki Tanaka, Michiro Iizuka, Hisashi Yano, Daisuke Mori, Daisuke Tsuboi, Tomoki Nishioka, Takashi Namba, Yukihiko Iizuka, Shimpei Kubota, Taku Nagai, Daisuke Ibi, Rui Wang, Atsushi Enomoto, Mayu Isotani-Sakakibara, Naoya Asai, Kazushi Kimura, Hiroshi Kiyonari, Takaya Abe, Akira Mizoguchi, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada, Kozo Kaibuchi
    HUMAN MOLECULAR GENETICS, 20(23) 4666-4683, Dec, 2011  Peer-reviewed
  • Nishioka Tomoki, Nakayama Masanori, Amano Mutsuki, Kaibuchi Kozo
    Abstracts for Annual Meeting of Japanese Proteomics Society, 2011 131-131, 2011  
  • Kuwata Ryo, Mori Daisuke, Tsuboi Daisuke, Nishioka Tomoki, Iizuka Yukihiko, Kuroda Keisuke, Yano Hisashi, Kubota Shinpei, Kaibuchi Kozo
    Journal of Pharmacological Sciences, 115 143P, 2011  Peer-reviewed
  • Norimichi Itoh, Masanori Nakayama, Takashi Nishimura, Shin Fujisue, Tomoki Nishioka, Takashi Watanabe, Kozo Kaibuchi
    CYTOSKELETON, 67(5) 297-308, May, 2010  Peer-reviewed

Misc.

 14
More

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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