Updated on 2024/04/01

写真a

 
SHIBATA, Hideki
 
Organization
Graduate School of Bioagricultural Sciences Department of Applied Biosciences Professor
Graduate School
Graduate School of Bioagricultural Sciences
Undergraduate School
School of Agricultural Sciences Department of Applied Biosciences
Title
Professor
Contact information
メールアドレス

Degree 2

  1. 博士(理学) （ 2001.9   神戸大学 ） 

  2. Master of Science

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Research Interests 1

  1. calcium-binding proteins, membrane traffic

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Research Areas 8

  1. Life Science / Applied biochemistry

  2. Life Science / Applied molecular and cellular biology

  3. Life Science / Functional biochemistry  / Functional Biochemistry

  4. Life Science / Cell biology

  5. Life Science / Molecular biology

  6. Life Science / Applied molecular and cellular biology

  7. Life Science / Applied biochemistry

  8. Life Science / Functional biochemistry

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Current Research Project and SDGs 2

  1. Functional analysis of calcium binding protein, ALG-2

  2. コラーゲン分泌を調節するカルシウム制御ネットワークの解析

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Research History 5

  1. Nagoya University   Graduate School of Bioagricultural Sciences   Associate professor

    2018.4

  2. Nagoya University   Graduate School of Bioagricultural Sciences Department of Applied Molecular Biosciences Division of Applied Biochemistry   Associate professor

    2014.5 - 2018.3

  3. 名古屋大学大学院生命農学研究科　助教

    2007.4 - 2010.11

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    Country：Japan

  4. 名古屋大学大学院生命農学研究科　助手

    2000.7 - 2007.3

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    Country：Japan

  5. 神戸大学理学部 助手

    1999.2 - 2000.6

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    Country：Japan

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Education 3

  1. Kobe University   Graduate School, Division of National Science and Technology

    1997.4 - 1999.1

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    Country： Japan

  2. Kobe University   Graduate School, Division of National Science and Technology   Biology

    - 1997.3

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    Country： Japan

  3. Kobe University   Faculty of Science   Department of Biology

    - 1995

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    Country： Japan

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Professional Memberships 8

  1. Japan Society for Bioscience, Biotechnology, and Agrochemistry

  2. The Japanese Biochemical Society

  3. 日本細胞生物学会

  4. The Molecular Biology Society of Japan

  5. THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

  6. THE JAPANESE BIOCHEMICAL SOCIETY

  7. JAPAN SOCIETY FOR CELL BIOLOGY

  8. JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY

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Awards 1

  1. 農芸化学奨励賞

    2011.5   日本農芸化学会  

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    Country：Japan

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Papers 85

  1. New Insights into the Regulation of mTOR Signaling via Ca<SUP>2+</SUP>-Binding Proteins Reviewed

    Amemiya Yuna, Maki Masatoshi, Shibata Hideki, Takahara Terunao

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 24 ( 4 )   2023.2

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    Language：English   Publisher：International Journal of Molecular Sciences  

    Environmental factors are important regulators of cell growth and proliferation. Mechanistic target of rapamycin (mTOR) is a central kinase that maintains cellular homeostasis in response to a variety of extracellular and intracellular inputs. Dysregulation of mTOR signaling is associated with many diseases, including diabetes and cancer. Calcium ion (Ca2+) is important as a second messenger in various biological processes, and its intracellular concentration is tightly regulated. Although the involvement of Ca2+ mobilization in mTOR signaling has been reported, the detailed molecular mechanisms by which mTOR signaling is regulated are not fully understood. The link between Ca2+ homeostasis and mTOR activation in pathological hypertrophy has heightened the importance in understanding Ca2+-regulated mTOR signaling as a key mechanism of mTOR regulation. In this review, we introduce recent findings on the molecular mechanisms of regulation of mTOR signaling by Ca2+-binding proteins, particularly calmodulin (CaM).

    DOI： 10.3390/ijms24043923

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  2. Hepatitis C virus (HCV)-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A. Reviewed International journal

    Lin Deng, Yujiao Liang, Adi Ariffianto, Chieko Matsui, Takayuki Abe, Masamichi Muramatsu, Takaji Wakita, Masatoshi Maki, Hideki Shibata, Ikuo Shoji

    Journal of virology   Vol. 96 ( 6 ) page： e0181121   2022.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. However, the roles of ROS/JNK activation in the HCV life cycle still remain unclear. We sought to identify a novel role of ROS/JNK signaling pathway in the HCV life cycle. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of Itch, a HECT-type E3 ubiquitin ligase, leading to activation of Itch. The siRNA-knockdown of Itch significantly reduced the extracellular HCV infectivity titers, HCV RNA, and HCV core protein without affecting intracellular HCV infectivity titers, HCV RNA, and HCV proteins, suggesting that Itch is involved in release of HCV particles. HCV-mediated JNK/Itch activation specifically promoted polyubiquitylation of an AAA-type ATPase VPS4A, but not VPS4B, required to form multivesicular bodies. Site-directed mutagenesis revealed that two lysine residues (K23 and K121) on VPS4A were important for VPS4A polyubiquitylation. The siRNA-knockdown of VPS4A, but not VPS4B, significantly reduced extracellular HCV infectivity titers. Co-immunoprecipitation analysis revealed that HCV infection specifically enhanced the interaction between CHMP1B, a subunit of endosomal sorting complexes required for transport (ESCRT)-III complex, and VPS4A, but not VPS4B, whereas VPS4A K23R/K121R greatly reduced the interaction with CHMP1B. HCV infection significantly increased ATPase activity of VPS4A, but not VPS4A K23R/K121R or VPS4B, suggesting that HCV-mediated polyubiquitylation of VPS4A contributes to activation of VPS4A. Taken together, we propose that HCV-induced ROS/JNK/Itch signaling pathway promotes VPS4A polyubiquitylation, leading to enhanced VPS4A-CHMP1B interaction and promotion of VPS4A ATPase activity, thereby promoting the release of HCV particles. IMPORTANCE ROS/JNK signaling pathway contributes to liver diseases, including steatosis, metabolic disorders, and hepatocellular carcinoma. We previously reported that HCV activates the ROS/JNK signaling pathway, leading to the enhancement of hepatic gluconeogenesis and apoptosis induction. This study further demonstrates that HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote release of HCV particles via polyubiquitylation of VPS4A. We provide evidence suggesting that HCV infection promotes the ROS/JNK/Itch signaling pathway and ESCRT/VPS4A machinery to release infectious HCV particles. Our results may lead to a better understanding of the mechanistic details of HCV particle release.

    DOI： 10.1128/jvi.01811-21

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  3. Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin. Reviewed International journal

    Yuna Amemiya, Nao Nakamura, Nao Ikeda, Risa Sugiyama, Chiaki Ishii, Masatoshi Maki, Hideki Shibata, Terunao Takahara

    International journal of molecular sciences   Vol. 22 ( 13 )   2021.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Here we report that amino acids also converge on regulation of the TSC2-Rheb GTPase axis via Ca2+/calmodulin (CaM). We showed that the amino acid-mediated increase of intracellular Ca2+ is important for mTORC1 activation and thereby contributes to the promotion of nascent protein synthesis. We found that Ca2+/CaM interacted with TSC2 at its GTPase activating protein (GAP) domain and that a CaM inhibitor reduced binding of CaM with TSC2. The inhibitory effect of a CaM inhibitor on mTORC1 activity was prevented by loss of TSC2 or by an active mutant of Rheb GTPase, suggesting that a CaM inhibitor acts through the TSC2-Rheb axis to inhibit mTORC1 activity. Taken together, in response to amino acids, Ca2+/CaM-mediated regulation of the TSC2-Rheb axis contributes to proper mTORC1 activation, in addition to the well-known lysosomal translocation of mTORC1 by Rag GTPases.

    DOI： 10.3390/ijms22136897

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  4. The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B Reviewed

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   Vol. 22 ( 3 ) page： 1 - 25   2021.2

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    DOI： 10.3390/ijms22031175

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  5. The Penta-EF-Hand ALG-2 Protein Interacts with the Cytosolic Domain of the SOCE Regulator SARAF and Interferes with Ubiquitination. Reviewed International journal

    Wei Zhang, Ayaka Muramatsu, Rina Matsuo, Naoki Teranishi, Yui Kahara, Terunao Takahara, Hideki Shibata, Masatoshi Maki

    International journal of molecular sciences   Vol. 21 ( 17 ) page： 1 - 21   2020.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    ALG-2 is a penta-EF-hand Ca2+-binding protein and interacts with a variety of proteins in mammalian cells. In order to find new ALG-2-binding partners, we searched a human protein database and retrieved sequences containing the previously identified ALG-2-binding motif type 2 (ABM-2). After selecting 12 high-scored sequences, we expressed partial or full-length GFP-fused proteins in HEK293 cells and performed a semi-quantitative in vitro binding assay. SARAF, a negative regulator of store-operated Ca2+ entry (SOCE), showed the strongest binding activity. Biochemical analysis of Strep-tagged and GFP-fused SARAF proteins revealed ubiquitination that proceeded during pulldown assays under certain buffer conditions. Overexpression of ALG-2 interfered with ubiquitination of wild-type SARAF but not ubiquitination of the F228S mutant that had impaired ALG-2-binding activity. The SARAF cytosolic domain (CytD) contains two PPXY motifs targeted by the WW domains of NEDD4 family E3 ubiquitin ligases. The PPXY motif proximal to the ABM-2 sequence was found to be more important for both in-cell ubiquitination and post-cell lysis ubiquitination. A ubiquitination-defective mutant of SARAF with Lys-to-Arg substitutions in the CytD showed a slower degradation rate by half-life analysis. ALG-2 promoted Ca2+-dependent CytD-to-CytD interactions of SARAF. The ALG-2 dimer may modulate the stability of SARAF by sterically blocking ubiquitination and by bridging SARAF molecules at the CytDs.

    DOI： 10.3390/ijms21176315

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  6. Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. Invited Reviewed International journal

    Terunao Takahara, Yuna Amemiya, Risa Sugiyama, Masatoshi Maki, Hideki Shibata

    Journal of biomedical science   Vol. 27 ( 1 ) page： 87 - 87   2020.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    The mechanistic target of rapamycin complex 1 (mTORC1) is an essential regulator of cell growth and metabolism through the modulation of protein and lipid synthesis, lysosome biogenesis, and autophagy. The activity of mTORC1 is dynamically regulated by several environmental cues, including amino acid availability, growth factors, energy levels, and stresses, to coordinate cellular status with environmental conditions. Dysregulation of mTORC1 activity is closely associated with various diseases, including diabetes, cancer, and neurodegenerative disorders. The discovery of Rag GTPases has greatly expanded our understanding of the regulation of mTORC1 activity by amino acids, especially leucine and arginine. In addition to Rag GTPases, other factors that also contribute to the modulation of mTORC1 activity have been identified. In this review, we discuss the mechanisms of regulation of mTORC1 activity by particular amino acids.

    DOI： 10.1186/s12929-020-00679-2

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  7. ATeam technology for detecting early signs of viral cytopathic effect

    DOYSABAS Karla Cristine C., OBA Mami, ISHIBASHI Tomoki, SHIBATA Hideki, TAKEMAE Hitoshi, SHIMODA Hiroshi, TARIGAN Ronald, MIZUTANI Tetsuya, IIDA Atsuo, HONDO Eiichi

    Journal of Veterinary Medical Science   Vol. 82 ( 3 ) page： 387 - 393   2020.3

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOCIETY OF VETERINARY SCIENCE  

    <p>Adenosine 5’-triphosphate (ATP), the major energy currency of the cell, is involved in many cellular processes, including the viral life cycle, and can be used as an indicator of early signs of cytopathic effect (CPE). In this study, we demonstrated that CPE can be analyzed using an FRET-based ATP probe named ATP indicator based on Epsilon subunit for Analytical Measurements (ATeam). The results revealed that as early as 3 hr, the virus infected cells showed a significantly different Venus/cyan fluorescent protein (CFP) ratio compared to the mock-infected cells. The ATeam technology is therefore useful to determine the early signs of ATP-based CPE as early as 3 hr without morphology-based CPE by light microscopy, and enables high throughput determination of the presence of microorganisms in neglected samples stored in laboratories.</p>

    DOI： 10.1292/jvms.20-0021

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  8. SH3YL1 cooperates with ESCRT-I in the sorting and degradation of the EGF receptor. Reviewed International journal

    Junya Hasegawa, Imen Jebri, Hikaru Yamamoto, Kazuya Tsujita, Emi Tokuda, Hideki Shibata, Masatoshi Maki, Toshiki Itoh

    Journal of cell science   Vol. 132 ( 19 )   2019.10

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    Ubiquitinated membrane proteins such as epidermal growth factor receptor (EGFR) are delivered to early endosomes and then sorted to lysosomes via multivesicular bodies (MVBs) for degradation. The regulatory mechanism underlying formation of intralumenal vesicles en route to generation of MVBs is not fully understood. In this study, we found that SH3YL1, a phosphoinositide-binding protein, had a vesicular localization pattern overlapping with internalized EGF in endosomes in the degradative pathway. Deficiency of SH3YL1 prevents EGF trafficking from early to late endosomes and inhibits degradation of EGFR. Moreover, we show that SH3YL1 mediates EGFR sorting into MVBs in a manner dependent on its C-terminal SH3 domain, which is necessary for the interaction with an ESCRT-I component, Vps37B. Taken together, our observations reveal an indispensable role of SH3YL1 in MVB sorting and EGFR degradation mediated by ESCRT complexes.

    DOI： 10.1242/jcs.229179

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  9. Exploring functions of the penta-EF-hand family by searching for calcium-dependent interacting factors Reviewed

    Maki Masatoshi, Takahara Terunao, Shibata Hideki

      Vol. 91 ( 2 ) page： 191 - 209   2019.4

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  10. Exploring functions of the penta-EF-hand family by searching for calcium-dependent interacting factors

      Vol. 91 ( 2 ) page： 191 - 209   2019.4

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  11. Adaptor functions of the Ca2+-binding protein ALG-2 in protein transport from the endoplasmic reticulum. Invited Reviewed International journal

    Hideki Shibata

    Bioscience, biotechnology, and biochemistry   Vol. 83 ( 1 ) page： 20 - 32   2019

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    Apoptosis-linked gene 2 (ALG-2) is a Ca2+-binding protein with five repetitive EF-hand motifs, named penta-EF-hand (PEF) domain. It interacts with various target proteins and functions as a Ca2+-dependent adaptor in diverse cellular activities. In the cytoplasm, ALG-2 is predominantly localized to a specialized region of the endoplasmic reticulum (ER), called the ER exit site (ERES), through its interaction with Sec31A. Sec31A is an outer coat protein of coat protein complex II (COPII) and is recruited from the cytosol to the ERES to form COPII-coated transport vesicles. I will overview current knowledge of the physiological significance of ALG-2 in regulating ERES localization of Sec31A and the following adaptor functions of ALG-2, including bridging Sec31A and annexin A11 to stabilize Sec31A at the ERES, polymerizing the Trk-fused gene (TFG) product, and linking MAPK1-interacting and spindle stabilizing (MISS)-like (MISSL) and microtubule-associated protein 1B (MAP1B) to promote anterograde transport from the ER.

    DOI： 10.1080/09168451.2018.1525274

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  12. High Sensitive Quantitative Binding Assays Using a Nanoluciferase-Fused Probe for Analysis of ALG-2-Interacting Proteins. Reviewed International journal

    Wei Zhang, Rina Matsuo, Terunao Takahara, Hideki Shibata, Masatoshi Maki

    Methods in molecular biology (Clifton, N.J.)   Vol. 1929   page： 501 - 516   2019

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    Many non-catalytic cellular proteins exert biological functions by formation of stable or transient complexes with other proteins. Analysis of the signal-induced physical interactions is important to understand their physiological roles in cells. Here we describe a biochemical method for assessing the binding of ALG-2 (gene name, PDCD6) to its target proteins that are immunoprecipitated from cell lysates. Application of nanoluciferase (Nluc)-fused ALG-2 enables a rapid quantitative evaluation of Ca2+-dependent interactions of target proteins with ALG-2 in vitro binding assays.

    DOI： 10.1007/978-1-4939-9030-6_31

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  13. Cellular Ca2+-Responding Nanoluciferase Reporter Gene System Directed by Tandemly Repeated Pseudo-palindromic NFAT-Response Elements. Reviewed International journal

    Wei Zhang, Terunao Takahara, Takuya Achiha, Hideki Shibata, Masatoshi Maki

    Methods in molecular biology (Clifton, N.J.)   Vol. 1929   page： 95 - 109   2019

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    Luciferase reporter gene systems based on the NFAT-response element (RE) have been used to monitor intracellular Ca2+ elevation. However, Ca2+ mobilization agent (e.g., ionomycin) alone is not adequate to activate the currently often employed reporter gene that contains the NFAT-RE found in the IL2 promoter. In addition to activation of NFAT through the Ca2+-calmodulin/calcineurin pathway, activation of AP-1 as a partner transcription factor is essential for the IL2-based NFAT-RE system. Here, we describe a detailed method for the recently developed new reporter gene system containing the NFAT-RE from the IL8 promoter. This system enables us to monitor endpoint effects of Ca2+-mobilizing agonists independent of AP-1 activation.

    DOI： 10.1007/978-1-4939-9030-6_7

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  14. Roles of ALG-2 in molecular transport from the endoplasmic reticulum

      Vol. 50 ( 8 ) page： 441 - 445   2018.7

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  15. A microtubule-associated protein MAP1B binds to and regulates localization of a calcium-binding protein ALG-2. Reviewed International journal

    Terunao Takahara, Yumika Arai, Yuta Kono, Hideki Shibata, Masatoshi Maki

    Biochemical and biophysical research communications   Vol. 497 ( 2 ) page： 492 - 498   2018.3

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    MAP1B (microtubule-associated protein 1B) binds to microtubules and regulates microtubule dynamics. Previously, we showed calcium-dependent interaction between MAP1B and a calcium-binding protein ALG-2 (apoptosis-linked gene 2), which is involved in regulation of the protein secretion pathway. Although ALG-2 generally binds to proteins through two consensus binding motifs such as ABM-1 and ABM-2, the absence of these motifs in MAP1B suggests a unique binding mode between MAP1B and ALG-2. Here, we identified the region of mouse MAP1B responsible for binding to ALG-2, and found point mutations that abrogated binding of MAP1B to ALG-2. Furthermore, interaction between MAP1B and ALG-2 selectively prevented ALG-2 from binding to proteins with ABM-2 such as Sec31A, suggesting competition between MAP1B and ABM-2-containing proteins for binding to ALG-2. Consistently, in MAP1B knockout cells, co-localization of ALG-2 with Sec31A was increased. Moreover, overexpression of wild-type MAP1B, but not the MAP1B mutant defective in ALG-2 binding, altered localizations of ALG-2 and Sec31A into dispersed distributions, suggesting that MAP1B regulates localizations of ALG-2 and Sec31A in the cells. Finally, we found two cancer-associated mutations of human MAP1B located near ALG-2 binding sites. The introduction of the corresponding mutations in mouse MAP1B dramatically reduced the binding ability to ALG-2. Thus, these results suggest that MAP1B plays a role in regulation of ALG-2 and Sec31A localizations, and that dysregulation of calcium-dependent binding of ALG-2 to MAP1B might influence pathological conditions such as cancers.

    DOI： 10.1016/j.bbrc.2018.02.048

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  16. Nanoluciferase Reporter Gene System Directed by Tandemly Repeated Pseudo-Palindromic NFAT-Response Elements Facilitates Analysis of Biological Endpoint Effects of Cellular Ca2+ Mobilization. Reviewed International journal

    Wei Zhang, Terunao Takahara, Takuya Achiha, Hideki Shibata, Masatoshi Maki

    International journal of molecular sciences   Vol. 19 ( 2 )   2018.2

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    NFAT is a cytoplasm-localized hyper-phosphorylated transcription factor that is activated through dephosphorylation by calcineurin, a Ca2+/calmodulin-dependent phosphatase. A non-palindromic NFAT-response element (RE) found in the IL2 promoter region has been commonly used for a Ca2+-response reporter gene system, but requirement of concomitant activation of AP-1 (Fos/Jun) often complicates the interpretation of obtained results. A new nanoluciferase (NanoLuc) reporter gene containing nine-tandem repeats of a pseudo-palindromic NFAT-RE located upstream of the IL8 promoter was designed to monitor Ca2+-induced transactivation activity of NFAT in human embryonic kidney (HEK) 293 cells by measuring luciferase activities of NanoLuc and co-expressed firefly luciferase for normalization. Ionomycin treatment enhanced the relative luciferase activity (RLA), which was suppressed by calcineurin inhibitors. HEK293 cells that stably express human STIM1 and Orai1, components of the store-operated calcium entry (SOCE) machinery, gave a much higher RLA by stimulation with thapsigargin, an inhibitor of sarcoplasmic/endoplamic reticulum Ca2+-ATPase (SERCA). HEK293 cells deficient in a penta-EF-hand Ca2+-binding protein ALG-2 showed a higher RLA value than the parental cells by stimulation with an acetylcholine receptor agonist carbachol. The novel reporter gene system is found to be useful for applications to cell signaling research to monitor biological endpoint effects of cellular Ca2+ mobilization.

    DOI： 10.3390/ijms19020605

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  17. 小胞体からの分子輸送におけるALG-2の役割

    柴田 秀樹

    月刊「細胞」   Vol. 50   page： 441 - 445   2018

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  18. The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins. Reviewed

    Terunao Takahara, Kuniko Inoue, Yumika Arai, Keiko Kuwata, Hideki Shibata, Masatoshi Maki

    Journal of Biological Chemistry   Vol. 292 ( 41 ) page： 17057-17072   2017.10

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    DOI： 10.1074/jbc.M117.800201.

  19. The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins. Reviewed International journal

    Terunao Takahara, Kuniko Inoue, Yumika Arai, Keiko Kuwata, Hideki Shibata, Masatoshi Maki

    The Journal of biological chemistry   Vol. 292 ( 41 ) page： 17057 - 17072   2017.10

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    Mobilization of intracellular calcium is essential for a wide range of cellular processes, including signal transduction, apoptosis, and vesicular trafficking. Several lines of evidence have suggested that apoptosis-linked gene 2 (ALG-2, also known as PDCD6), a calcium-binding protein, acts as a calcium sensor linking calcium levels with efficient vesicular trafficking, especially at the endoplasmic reticulum (ER)-to-Golgi transport step. However, how ALG-2 regulates these processes remains largely unclear. Here, we report that MAPK1-interacting and spindle-stabilizing (MISS)-like (MISSL), a previously uncharacterized protein, interacts with ALG-2 in a calcium-dependent manner. Live-cell imaging revealed that upon a rise in intracellular calcium levels, GFP-tagged MISSL (GFP-MISSL) dynamically relocalizes in a punctate pattern and colocalizes with ALG-2. MISSL knockdown caused disorganization of the components of the ER exit site, the ER-Golgi intermediate compartment, and Golgi. Importantly, knockdown of either MISSL or ALG-2 attenuated the secretion of secreted alkaline phosphatase (SEAP), a model secreted cargo protein, with similar reductions in secretion by single- and double-protein knockdowns, suggesting that MISSL and ALG-2 act in the same pathway to regulate the secretion process. Furthermore, ALG-2 or MISSL knockdown delayed ER-to-Golgi transport of procollagen type I. We also found that ALG-2 and MISSL interact with microtubule-associated protein 1B (MAP1B) and that MAP1B knockdown reverts the reduced secretion of SEAP caused by MISSL or ALG-2 depletion. These results suggest that a change in the intracellular calcium level plays a role in regulation of the secretory pathway via interaction of ALG-2 with MISSL and MAP1B.

    DOI： 10.1074/jbc.M117.800201

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  20. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis Reviewed

    Bradley N. Smith, Simon D. Topp, Claudia Fallini, Hideki Shibata, Han-Jou Chen, Claire Troakes, Andrew King, Nicola Ticozzi, Kevin P. Kenna, Athina Soragia-Gkazi, Jack W. Miller, Akane Sato, Diana Marques Dias, Maryangel Jeon, Caroline Vance, Chun Hao Wong, Martina de Majo, Wejdan Kattuah, Jacqueline C. Mitchell, Emma L. Scotter, Nicholas W. Parkin, Peter C. Sapp, Matthew Nolan, Peter J. Nestor, Michael Simpson, Michael Weale, Monkel Lek, Frank Baas, J. M. Vianney de Jong, Anneloor L. M. A. ten Asbroek, Alberto Garcia Redondo, Jesus Esteban-Perez, Cinzia Tiloca, Federico Verde, Stefano Duga, Nigel Leigh, Hardev Pall, Karen E. Morrison, Ammar Al-Chalabi, Pamela J. Shaw, Janine Kirby, Martin R. Turner, Kevin Talbot, Orla Hardiman, Jonathan D. Glass, Jacqueline de Belleroche, Masatoshi Maki, Stephen E. Moss, Christopher Miller, Cinzia Gellera, Antonia Ratti, Safa Al-Sarraj, Robert H. Brown, Vincenzo Silani, John E. Landers, Christopher E. Shaw

    SCIENCE TRANSLATIONAL MEDICINE   Vol. 9 ( 388 ) page： eaad9157   2017.5

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.

    DOI： 10.1126/scitranslmed.aad9157

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  21. The calcium-binding protein ALG-2 promotes endoplasmic reticulum exit site localization and polymerization of Trk-fused gene (TFG) protein. Reviewed International journal

    Takashi Kanadome, Hideki Shibata, Keiko Kuwata, Terunao Takahara, Masatoshi Maki

    The FEBS journal   Vol. 284 ( 1 ) page： 56 - 76   2017.1

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    Apoptosis-linked gene 2 (ALG-2), which is a gene product of PDCD6, is a 22-kDa Ca2+ -binding protein. Accumulating evidence points to a role for ALG-2 as a Ca2+ -responsive adaptor protein. On binding to Ca2+ , ALG-2 undergoes a conformational change that facilitates its interaction with various proteins. It also forms a homodimer and heterodimer with peflin, a paralog of ALG-2. However, the differences in cellular roles for the ALG-2 homodimer and ALG-2/peflin heterodimer are unclear. In the present study, we found that Trk-fused gene (TFG) protein interacted with the ALG-2 homodimer. Immunostaining analysis revealed that TFG and ALG-2 partially overlapped at endoplasmic reticulum exit sites (ERES), a platform for COPII-mediated protein transport from the endoplasmic reticulum. Time-lapse live-cell imaging demonstrated that both green fluorescent protein-fused TFG and mCherry-fused ALG-2 are recruited to ERES after thapsigargin treatment, which raises intracellular Ca2+ levels. Furthermore, overexpression of ALG-2 induced the accumulation of TFG at ERES. TFG has an ALG-2-binding motif and deletion of the motif decreased TFG binding to ALG-2 and shortened its half-life at ERES, suggesting a critical role for ALG-2 in retaining TFG at ERES. We also demonstrated, by in vitro cross-linking assays, that ALG-2 promoted the polymerization of TFG in a Ca2+ -dependent manner. Collectively, the results suggest that ALG-2 acts as a Ca2+ -sensitive adaptor to concentrate and polymerize TFG at ERES, supporting a potential role for ALG-2 in COPII-dependent trafficking from the endoplasmic reticulum.

    DOI： 10.1111/febs.13949

    Web of Science

    Scopus

    PubMed

  22. Multifaceted Roles of ALG-2 in Ca2+-Regulated Membrane Trafficking. Reviewed

    Masatoshi Maki, Terunao Takahara, Hideki Shibata

    International Journal of Molecular Sciences   Vol. 17 ( 9 ) page： E1401   2016.8

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    DOI： 10.3390/ijms17091401.

  23. Tubby-like protein superfamily member PLSCR3 functions as a negative regulator of adipogenesis in mouse 3T3-L1 preadipocytes by suppressing induction of late differentiation stage transcription factors. Reviewed

    Akira Inokawa, Tatsutoshi Inuzuka, Terunao Takahara, Hideki Shibata, Masatoshi Maki

    Bioscience Reports   Vol. 36 ( 1 ) page： e00287   2016.1

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    DOI： 10.1042/BSR20150215

  24. A New Role for Annexin A11 in the Early Secretory Pathway via Stabilizing Sec31A Protein at the Endoplasmic Reticulum Exit Sites (ERES). Reviewed

    Hideki Shibata, Takashi Kanadome, Hirofumi Sugiura, Takeru Yokoyama, Minami Yamamuro, Stephen E. Moss, Masatoshi Maki

    The Journal of Biological Chemistry   Vol. 290 ( 8 ) page： 4981-4993   2015.2

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    DOI： 10.1074/jbc.M114.592089

  25. Structural Analysis of the Complex between Penta-EF-Hand ALG-2 Protein and Sec31A Peptide Reveals a Novel Target Recognition Mechanism of ALG-2 Reviewed

    Takeshi Takahashi, Kyosuke Kojima, Wei Zhang, Kanae Sasaki, Masaru Ito, Hironori Suzuki, Masato Kawasaki, Soichi Wakatsuki, Terunao Takahara, Hideki Shibata, Masatoshi Maki

    International Journal of Molecular Sciences   Vol. 16 ( 2 ) page： 3677-3699   2015.2

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    DOI： 10.3390/ijms16023677

  26. Involvement of calpain-7 in epidermal growth factor receptor degradation via the endosomal sorting pathway. Reviewed

    Yuki Maemoto, Yasuko Ono, Satomi Kiso, Hideki Shibata, Terunao Takahara, Hiroyuki Sorimachi, Masatoshi Maki

    FEBS J.   Vol. 281 ( 16 ) page： 3642-3655   2014.7

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  27. Nuclear ALG-2 protein interacts with Ca2+ homeostasis endoplasmic reticulum protein (CHERP) Ca2+-dependently and participates in regulation of alternative splicing of inositol trisphosphate receptor type 1 (IP3R1) pre-mRNA. Reviewed

    Kanae Sasaki-Osugi, Chiaki Imoto, Terunao Takahara, Hideki Shibata, Masatoshi Maki

    J. Biol. Chem.   Vol. 288 ( 46 ) page： 33361-33375   2013.9

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  28. VPS37 isoforms differentially modulate the ternary complex formation of ALIX, ALG-2, and ESCRT-I. Reviewed

    Mayumi Okumura, Angela M. Katsuyama, Hideki Shibata, Masatoshi Maki

    Biosci. Biotechnol. Biochem.   Vol. 77 ( 8 ) page： 1715-1721   2013.8

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  29. Identification of phosphorylation sites in the C-terminal region of charged multivesicular body protein 1A (CHMP1A). Reviewed

    Yuki Maemoto, Hideki Shibata, Masatoshi Maki

    Biosci. Biotechnol. Biochem.   Vol. 77 ( 6 ) page： 1317-1319   2013.6

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  30. Mammalian ESCRT-III-related protein IST1 has a distinctive Met-Pro repeat sequence that is essential for interaction with ALG-2 in the presence of Ca2+. Reviewed

    Mayumi Okumura, Takeshi Takahashi, Hideki Shibata, Masatoshi Maki

    Biosci. Biotechnol. Biochem.   Vol. 77 ( 5 ) page： 1049-1054   2013.5

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  31. Analysis of limited proteolytic activity of calpain-7 using non-physiological substrates in mammalian cells. Reviewed

    Yuki Maemoto, Satomi Kiso, Hideki Shibata, Masatoshi Maki

    FEBS J.   Vol. 280 ( 11 ) page： 2594-2607   2013.4

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  32. ALG-2-interacting Tubby-like protein superfamily member PLSCR3 is secreted by an exosomal pathway and taken up by recipient cultured cells. Reviewed

    Tatsutoshi Inuzuka, Akira Inokawa, Cen Chen, Kumiko Kizu, Hiroshi Narita, Hideki Shibata, Masatoshi Maki

    Biosci. Rep.   Vol. 33 ( 2 ) page： e00026   2013.3

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  33. Biochemical and immunological detection of physical interactions between penta-EF-hand protein ALG-2 and its binding partners. Reviewed

    Kanae Osugi, Hideki Shibata, Masatoshi Maki

    Methods Mol Biol.   Vol. 963   page： 187-200   2012.11

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    DOI： 10.1007/978-1-62703-230-8_12.

  34. Prediction of a New Ligand-Binding Site for Type 2 Motif based on the Crystal Structure of ALG-2 by Dry and Wet Approaches. Reviewed

    Takeshi Takahashi, Hironori Suzuki, Tatsutoshi Inuzuka, Hideki Shibata, Masatoshi Maki

    Int J Mol Sci.   Vol. 13 ( 6 ) page： 7535-7549   2012.6

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  35. Identification of the P-body component PATL1 as a novel ALG-2-interacting protein by in silico and far-Western screening of proline-rich proteins. Reviewed

    Kanae Osugi, Hironori Suzuki, Tomomi Nomura, Yasuo Ariumi, Hideki Shibata, Masatoshi Maki

    J Biochem.   Vol. 151 ( 6 ) page： 657-666   2012.6

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  36. Evolutionary and physical linkage between calpains and penta-EF-hand Ca2+-binding proteins. Reviewed

    Masatoshi Maki, Yuki Maemoto, Yohei Osako, Hideki Shibata

    FEBS J.   Vol. 279 ( 8 ) page： 1414-1421   2012.4

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    DOI： 10.1111/j.1742-4658.2012.08560.x.

  37. Calpain-7 binds to CHMP1B at its second α-helical region and forms a ternary complex with IST1. Reviewed

    Yuki Maemoto, Yohei Osako, Emi Goto, Eri Nozawa, Hideki Shibata, Masatoshi Maki

    J. Biochem.   Vol. 150 ( 4 ) page： 411-421   2011.10

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  38. Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein. Reviewed

    Masatoshi Maki, Hironori Suzuki, Hideki Shibata

    Sci China Life Sci.   Vol. 54 ( 8 ) page： 770-779   2011.8

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  39. Autolytic activity of human calpain 7 is enhanced by ESCRT-III-related protein IST1 through MIT-MIM interaction. Reviewed

    Yohei Osako, Yuki Maemoto, Ryohei Tanaka, Hironori Suzuki, Hideki Shibata, Masatoshi Maki

    FEBS J.   Vol. 277 ( 21 ) page： 4412-4426   2010.11

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  40. *The ALG-2 binding site in Sec31A influences the retention kinetics of Sec31A at the endoplasmic reticulum exit sites as revealed by live-cell time-lapse imaging. Reviewed

    Shibata H, Inuzuka T, Yoshida H, Sugiura H, Wada I, Maki M.

    Biosci Biotechnol Biochem.   Vol. 74 ( 9 ) page： 1819-1826   2010.9

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    ALG-2, a member of the penta-EF-hand protein family, interacts Ca²+-dependently with a COPII component, Sec31A. In this study, we first established HeLa cells stably expressing green fluorescent protein-fused ALG-2 (GFP-ALG-2) and red fluorescent protein-fused Sec31A (Sec31A-RFP). After inducing Ca²+-mobilization, the cytoplasmic distribution of GFP-ALG-2 changed from a diffuse to a punctate pattern, which extensively overlapped with the Sec31A-RFP-positive structures, indicating that ALG-2 is recruited to the endoplasmic reticulum exit sites (ERES) in living cells. Next, overlay experiments with biotin-labeled ALG-2 were done to dissect the ALG-2 binding site (ABS). They revealed that a sequence comprising amino acid residues 839-851 in the Pro-rich region was necessary and sufficient for direct binding to ALG-2. Finally, fluorescence recovery after photobleaching analysis indicated that the ABS deletion reduced the high-affinity population of Sec31A to the ERES, suggesting that the ABS is one of the key determinants of the retention kinetics of Sec31A at ERES.

  41. Distinct functions of human MVB12A and MVB12B in the ESCRT-I dependent on their posttranslational modifications. Reviewed

    Takumi Tsunematsu, Emiko Yamauchi, Hideki Shibata, Masatoshi Maki, Takeshi Ohta, Hiroaki Konishi

    Biochem. Biophys. Res. Commun.   Vol. 399 ( 2 ) page： 232-237   2010.8

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  42. Molecular basis for defect in Alix-binding by alternatively spliced isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in target recognition. Reviewed

    Tatsutoshi Inuzuka, Hironori Suzuki, Masato Kawasaki, Hideki Shibata, Soichi Wakatsuki, Masatoshi Maki

    BMC Struct. Biol.   Vol. 10   2010.8

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    DOI： doi:10.1186/1472-6807-10-25

  43. *Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor that bridges Alix and TSG101. Reviewed

    Okumura M, Ichioka F, Kobayashi R, Suzuki H, Yoshida H, Shibata H, Maki M.

    Biochem Biophys Res Commun.   Vol. 386 ( 1 ) page： 237-241   2009.8

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  44. The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures. Reviewed

    Suzuki H, Kawasaki M, Inuzuka T, Okumura M, Kakiuchi T, Shibata H, Wakatsuki S, Maki M.

    Biochem Soc Trans.   Vol. 37 ( Pt1 ) page： 190-194   2009.2

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  45. Crystallization and X-ray diffraction analysis of N-terminally truncated human ALG-2. Reviewed

    Hironori Suzuki, Masato Kawasaki, Tatsutoshi Inuzuka, Mayumi Okumura, Takeshi Kakiuchi, Hideki Shibata, Soichi Wakatsuki, Masatoshi Maki

    Acta Crystallogr Sect F Struct Biol Cryst Commun.   Vol. 64 ( Pt11 ) page： 974-977   2008.11

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  46. *Structural basis for Ca2+-dependent formation of ALG-2/Alix peptide complex: Ca2+/EF3-driven arginine switch mechanism. Reviewed

    Hironori Suzuki, Masato Kawasaki, Tatsutoshi Inuzuka, Mayumi Okumura, Takeshi Kakiuchi, Hideki Shibata, Soichi Wakatsuki, Masatoshi Maki

    Structure   Vol. 16 ( 10 ) page： 1562-1573   2008.10

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  47. *Human calpain7/PalBH associates with a subset of ESCRT-III-related proteins in its N-terminal region and partly localizes to endocytic membrane compartments. Reviewed

    Chiharu Yorikawa, Emi Takaya, Yohei Osako, Ryohei Tanaka, Yoshinori Terasawa, Takao Hamakubo, Yasuhiro Mochizuki, Hiroko Iwanari, Tatsuhiko Kodama, Tatsuya Maeda, Kiyotaka Hitomi, Hideki Shibata, Masatoshi Maki

    J. Biochem.   Vol. 143 ( 6 ) page： 731-745   2008.6

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  48. *Identification of Alix-type and Non-Alix-type ALG-2-binding sites in human phospholipid scramblase 3: differential binding to an alternatively spliced isoform and amino acid-substituted mutants. Reviewed

    Hideki Shibata, Hironori Suzuki, Takeshi Kakiuchi, Tatsutoshi Inuzuka, Haruna Yoshida, Takako Mizuno, Masatoshi Maki

    J. Biol. Chem.   Vol. 283 ( 15 ) page： 9623-9632   2008.4

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  49. Brox, a novel farnesylated Bro1 domain-containing protein that associates with charged multivesicular body protein 4 (CHMP4). Reviewed

    Fumitaka Ichioka, Ryota Kobayashi, Keiichi Katoh, Hideki Shibata, Masatoshi Maki

    FEBS J.   Vol. 275 ( 4 ) page： 682-692   2008.2

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  50. Identification of substrates for transglutaminase in Physarum polycephalum, an acellular slime mold, upon cellular mechanical damage. Reviewed

    Fumitaka Wada, Hiroki Hasegawa, Akio Nakamura, Yoshiaki Sugimura, Yoshiki Kawai, Narie Sasaki, Hideki Shibata, Masatoshi Maki, Kiyotaka Hitomi

    FEBS J.   Vol. 274 ( 11 ) page： 2766-2777   2007.4

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  51. *ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner. Reviewed

    Hideki Shibata, Hironori Suzuki, Haruna Yoshida, Masatoshi Maki

    Biochem. Biophys. Res. Commun.   Vol. 353 ( 3 ) page： 756-763   2007.2

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  52. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Reviewed

    Fumitaka Ichioka, Emi Takaya, Hironori Suzuki, Sachiko Kajigaya, Vladimir L. Buchman, Hideki Shibata, Masatoshi Maki

    Arch. Biochem. Biophys.   Vol. 457 ( 2 ) page： 142-149   2007.1

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  53. The penta-EF-hand protein ALG-2 and its interacting proteins. Reviewed

    Masatoshi Maki, Hideki Shibata

    Calcium Binding Proteins   Vol. 2   page： 4-10   2007

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  54. CHMP7, a novel ESCRT-III-related protein, associates with CHMP4b and functions in the endosomal sorting pathway. Reviewed

    Mio Horii, Hideki Shibata, Ryota Kobayashi, Keiichi Katoh, Chiharu Yorikawa, Jiro Yasuda, Masatoshi Maki

    Biochem. J.   Vol. 400 ( 1 ) page： 23-32   2006.11

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  55. Reevaluation of the Predicted Gene Structure of Dictyostelium Cyctatin A3 (cpiC) by Nucleotide Sequence Determination of its cDNA and its Phylogenetic Position in the Cyctatin Superfamily Reviewed

    Medhat S. El-Halawany, Hideki Shibata, Kiyotaka Hitomi, Masatoshi Maki

    Molecular Biology Reports   Vol. 32 ( 4 ) page： 257-264   2005.12

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  56. The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B Reviewed

    Keiichi Katoh, Hidenori Suzuki, Yoshinori Terasawa, Takako Mizuno, Jiro Yasuda, Hideki Shibata, Masatoshi Maki

    Biochemical Journal   Vol. 391 ( Pt 3 ) page： 677-685   2005.11

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  57. Identification of Rab GTPase-Activating Protein-Like Protein (RabGAPLP) as a Novel Alix/AIP1-Interacting Protein Reviewed

    Fumitaka Ichioka, Mio Horii, Keiichi Katoh, Yoshinori Terasawa, Hideki Shibata, Masatoshi Maki

    Bioscience, Biotechnology, and Biochemistry   Vol. 69 ( 4 ) page： 861-865   2005.4

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  58. Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting Reviewed

    Chiharu Yorikawa, Hideki Shibata, Satoshi Waguri, Kazumi Hatta, Mio Horii, Keiichi Katoh, Toshihide Kobayashi, Yasuo Uchiyama, Masatoshi Maki

    Biochemical Journal   Vol. 387 ( Pt 1 ) page： 17-26   2005.4

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  59. Dictyostelium discoideum requires an Alix/AIP1 homolog, DdAlix, for morphogenesis in alkaline environments Reviewed

    Susumu Ohkouchi, Hajime Saito, Fumika Aruga, Tatsuya Maeda, Hideki Shibata, Masatoshi Maki

    FEBS Letters   Vol. 579 ( 7 ) page： 1745-1750   2005.3

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  60. DdAlix, an Alix/AIP1 homolog in Dictyostelium discoideum, is required for multicellular development under low Ca2+ conditions Reviewed

    Susumu Ohkouchi, Medhat S. El-Halawany, Fumika Aruga, Hideki Shibata, Kiyotaka Hitomi, Masatoshi Maki

    Gene   Vol. 337   page： 131-139   2004.8

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  61. Identification of cysteine protease inhibitors that belong to cystatin family 1 in the cellular slime mold Dictyostelium discoideum Reviewed

    Medhat S. El-Halawany, Susumu Ohkouchi, Hideki Shibata, Kiyotaka Hitomi, Masatoshi Maki

    Biological Chemistry   Vol. 385 ( 6 ) page： 547-550   2004.6

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  62. Protein kinase PKN1 associates with TRAF2 and is involved in TRAF2-NF-kappaB signaling pathway Reviewed

    Yusuke Gotoh, Kumiko Oishi, Hideki Shibata, Akiko Yamagiwa, Takayuki Isagawa, Tamako Nishimura, Emiko Goyama, Mikiko Takahashi, Hideyuki Mukai, Yoshitaka Ono

    Biochemical and Biophysical Research Communications   Vol. 314 ( 3 ) page： 688-694   2004.2

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  63. The Penta-EF-Hand Protein ALG-2 Interacts with a Region Containing PxY Repeats in Alix/AIP1, Which Is Required for the Subcellular Punctate Distribution of the Amino-Terminal Truncation Form of Alix/AIP1 Reviewed

    Hideki Shibata, Keiko Yamada, Takako Mizuno, Chiharu Yorikawa, Hiroshi Takahashi, Hirokazu Satoh, Yasuyuki Kitaura, Masatoshi Maki

    The Journal of Biochemistry   Vol. 135 ( 1 ) page： 117-128   2004.1

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  64. CHMP4b is a major binding partner of the ALG-2-interacting protein Alix among the three CHMP4 isoforms Reviewed

    Keiichi Katoh, Hideki Shibata, Kazumi Hatta, Masatoshi Maki

    Archives of Biochemistry and Biophysics   Vol. 421 ( 1 ) page： 159-165   2004.1

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  65. The ALG-2-interacting Protein Alix Associates with CHMP4b, a Human Homologue of Yeast Snf7 That Is Involved in Multivesicular Body Sorting Reviewed

    Keiichi Katoh, Hideki Shibata, Hidenori Suzuki, Atsuki Nara, Kazumi Ishidoh, Eiki Kominami, Tamotsu Yoshimori, Masatoshi Maki

    The Journal of Biological Chemistry   Vol. 278 ( 40 ) page： 39104-39113   2003.10

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  66. The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner Reviewed

    Hirokazu Satoh, Yoshimi Nakano, Hideki Shibata, Masatoshi Maki

    Biochimica et Biophysica Acta   Vol. 1600 ( 1-2 ) page： 61-67   2002.11

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  67. Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins Reviewed

      Vol. 1600 ( 1-2 ) page： 51-60   2002.11

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  68. ALG-2 Interacts with the Amino-Terminal Domain of Annexin XI in a Ca2+-Dependent Manner Reviewed

    Hirokazu Satoh, Hideki Shibata, Yoshimi Nakano, Yasuyuki Kitaura, Masatoshi Maki

    Biochemical and Biophysical Research Communications   Vol. 291 ( 5 ) page： 1166-1172   2002.3

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  69. Both ALG-2 and Peflin, Penta-EF-hand (PEF) Proteins, Are Stabilized by Dimerization through Their Fifth EF-Hand Regions Reviewed

    Yasuyuki Kitaura, Hirokazu Satoh, Hiroshi Takahashi, Hideki Shibata, Masatoshi Maki

    Archives of Biochemistry and Biophysics   Vol. 399 ( 1 ) page： 12-18   2002.3

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  70. PKNbeta Interacts with the SH3 Domains of Graf and a Novel Graf Related Protein, Graf2, Which Are GTPase Activating Proteins for Rho Family Reviewed

    Hideki Shibata, Kumiko Oishi, Akiko Yamagiwa, Mikiko Matsumoto, Hideyuki Mukai, Yoshitaka Ono

    The Journal of Biochemistry   Vol. 130 ( 1 ) page： 23-31   2001.7

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  71. Interaction of PKN with a neuron-specific basic helix-loop-helix transcription factor, NDRF/NeuroD2 Reviewed

    Hideki Shibata, Hisanobu Oda, Hideyuki Mukai, Kumiko Oishi, Kazuyo Misaki, Hiroaki Ohkubo, Yoshitaka Ono

    Brain Reserch Molecular Brain Reserch   Vol. 74 ( 1-2 ) page： 126-134   1999.12

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  72. Identification and characterization of PKNbeta, a novel isoform of protein kinase PKN: expression and arachidonic acid dependency are different from those of PKNalpha Reviewed

    Kumiko Oishi, Hideyuki Mukai, Hideki Shibata, Mikiko Takahashi, Yoshitaka Ono

    Biochemical and Biophysical Research Communications   Vol. 261 ( 3 ) page： 808-814   1999.8

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  73. Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the golgi apparatus Reviewed

    Mikiko Takahashi, Hideki Shibata, Masaki Shimakawa, Masaaki Miyamoto, Hideyuki Mukai, Yoshitaka Ono

    The Journal of Biological Chemistry   Vol. 274 ( 24 ) page： 17267-17274   1999.6

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  74. Interaction of the small G protein RhoA with the C terminus of human phospholipase D1 Reviewed

    "Masakazu Yamazaki, Yue Zhang, Hiroshi Watanabe, Takeaki Yokozeki, Shigeo Ohno, Kozo Kaibuchi, Hideki Shibata, Hideyuki Mukai, Yoshitaka Ono, Michael A. Frohman, Yasunori Kanaho"

    The Journal of Biological Chemistry   Vol. 274 ( 10 ) page： 6035-6038   1999.3

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  75. PKN interacts with a paraneoplastic cerebellar degeneration-associated antigen, which is a potential transcription factor Reviewed

    Hiromi Takanaga, Hideyuki Mukai, Hideki Shibata, Masanao Toshimori, Yoshitaka Ono

    Experimental Cell Research   Vol. 241 ( 2 ) page： 363-372   1998.6

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  76. Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN Reviewed

    Kaori Matsuzawa, Hidetaka Kosako, Naoyuki Inagaki, Hideki Shibata, Hideyuki Mukai, Yoshitaka Ono, Mutsuki Amano, Kozo Kaibuchi, Yoshiharu Matsuura, Ichiro Azuma, Masaki Inagaki

    Biochemical and Biophysical Research Communications   Vol. 234 ( 3 ) page： 621-625   1997.5

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  77. Interaction of PKN with alpha-actinin Reviewed

    Hideyuki Mukai, Masanao Toshimori, Hideki Shibata, Hiromi Takanaga, Michinori Kitagawa, Masako Miyahara, Masaki Shimakawa, Yoshitaka Ono

    The Journal of Biological Chemistry   Vol. 272 ( 8 ) page： 4740-4746   1997.2

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  78. Translocation of PKN from the cytosol to the nucleus induced by stresses Reviewed

    Hideyuki Mukai, Masako Miyahara, Hiroko Sunakawa, Hideki Shibata, Masanao Toshimori, Michinori Kitagawa, Masaki Shimakawa, Hiromi Takanaga, Yoshitaka Ono

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 93 ( 19 ) page： 10195-10199   1996.9

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  79. Characterization of the interaction between RhoA and the amino-terminal region of PKN. Reviewed

    Hideki Shibata, Hideyuki Mukai,Yoshimasa Inagaki, Yoshimi Homma, Kazushi Kimura, Kozo Kaibuchi, Shuh Narumiya, Yoshitaka Ono

    FEBS Letters   Vol. 385 ( 3 ) page： 221-224   1996.5

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    Language：English   Publishing type：Research paper (scientific journal)  

  80. PKN associates and phosphorylates the head-rod domain of neurofilament protein Reviewed

    Hideyuki Mukai, Masanao Toshimori, Hideki Shibata, Michinori Kitagawa, Masaki Shimakawa, Masako Miyahara, Hiroko Sunakawa, Yoshitaka Ono

    The Journal of Biological Chemistry   Vol. 271 ( 16 ) page： 9816-9822   1996.4

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    Language：English   Publishing type：Research paper (scientific journal)  

  81. The role of the unique motifs in the amino-terminal region of PKN on its enzymatic activity Reviewed

    Michinori Kitagawa, Hideki Shibata, Masanao Toshimori, Hideyuki Mukai, Yoshitaka Ono

    Biochemical and Biophysical Research Communications   Vol. 220 ( 3 ) page： 963-968   1996.3

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    Language：English   Publishing type：Research paper (scientific journal)  

  82. Identification of Schizosaccharomyces pombe gene psk1+, encoding a novel putative serine/threonine protein kinase, whose mutation conferred resistance to phenylarsine oxide." Reviewed

    Hideyuki Mukai, Masako Miyahara, Hiromi Takanaga, Michinori Kitagawa, Hideki Shibata, Masaki Shimakawa, Yoshitaka Ono

    Gene   Vol. 166 ( 1 ) page： 155-159   1995.12

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    Language：English   Publishing type：Research paper (scientific journal)  

  83. Purification and characterization of a fatty acid-activated protein kinase (PKN) from rat testis Reviewed

    Michinori Kitagawa, Hideyuki Mukai, Hideki Shibata, Yoshitaka Ono"

    Biochemical Journal   Vol. 310 ( Pt 2 ) page： 657-664   1995.9

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    Language：English   Publishing type：Research paper (scientific journal)  

  84. Xenopus PKN: cloning and sequencing of the cDNA and identification of conserved domains Reviewed

    Hideyuki Mukai, Kazuya Mori, Hiromi Takanaga, Michinori Kitagawa, Hideki Shibata, Masaki Shimakawa, Masako Miyahara, Yoshitaka Ono"

    Biochimica et Biophysica Acta   Vol. 1261 ( 2 ) page： 296-300   1995.4

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    Language：English   Publishing type：Research paper (scientific journal)  

  85. Activation of PKN, a novel 120-kDa protein kinase with leucine zipper- like sequences, by unsaturated fatty acids and by limited proteolysis Reviewed

    Biochemical and Biophysical Research Communications   Vol. 204 ( 1 ) page： 348-356   1994.10

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    Language：English   Publishing type：Research paper (scientific journal)  

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To the head of Papers.▲

Books 3

  1. カルシウム依存的相互作用因子から探るpenta-EF-handファミリーの機能 Reviewed

    牧正敏，高原照直，柴田秀樹（ Role： Joint author）

    日本生化学会  2019.4 

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    Total pages：191-209   Language：Japanese Book type：Scholarly book

    DOI： 10.14952/SEIKAGAKU.2019.910191

  2. 小胞体からの分子輸送におけるALG-2の役割 Reviewed

    柴田秀樹, 高原照直, 京卓志, 牧正敏（ Role： Joint author）

    北隆館／ニュー・サイエンス社  2018.6 

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    Language：Japanese Book type：Scholarly book

  3. 「エンドソームでの輸送選別に働くESCRT装置」メンブレントラフィック : 膜・小胞による細胞内輸送ネットワーク（第6章） Reviewed

    柴田秀樹, 牧正敏（ Role： Joint author）

    化学同人  2016.7  （ ISBN:9784759817232 ）

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    Language：Japanese Book type：Textbook, survey, introduction

To the head of Books.▲

MISC 21

  1. ALS原因遺伝子産物TDP-43の定量的解析を目的としたモデル培養細胞の開発

    舟橋里帆、高原照直、牧正敏、柴田秀樹

    日本農芸化学会2022年度（令和4年度）大会     2022.3

    　More details

    Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)  

  2. 細胞成長制御を司る mTORC1 経路の新規制御因子の探索と同定

    小林海咲、石井千愛、牧正敏、柴田秀樹、高原照直

    日本農芸化学会中部支部第190回例会     2021.9

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    Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)  

  3. 動物細胞のアミノ酸応答におけるカルシウムの作用機序の解明

    雨宮優奈、池田奈央、柴田秀樹、牧正敏、高原照直

    日本農芸化学会中部支部第190回例会     2021.9

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    Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)  

  4. 動物細胞の成長制御を司るmTORC1経路のCa2+シグナルによる調節機構の解析

    雨宮優奈、池田奈央、牧正敏、柴田秀樹、高原照直

    第85回日本生化学会中部支部例会・シンポジウム     2021.5

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    Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)  

  5. 損傷リソソームへのCa2+結合タンパク質ALG-2動員の分子機構解析

    川野琢己, 舟橋里帆, 森花菜子, 桑田啓子, 牧正敏, 高原照直, 柴田秀樹

    第43回日本分子生物学会年会     2020.12

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    Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)  

  6. アミノ酸応答シグナル経路におけるカルシウムを介した新規制御機構の解明

    雨宮優奈, 池田奈央, 柴田秀樹, 牧正敏, 高原照直

    第187回日本農芸化学会中部支部例会     2020.9

  7. ストア作動性カルシウム流入制御因子SARAFの二量体形成におけるALG-2の役割

    河原由衣, 高原照直, 柴田秀樹, 牧正敏

    第187回日本農芸化学会中部支部例会     2020.9

  8. 近接依存性標識法を用いた初期分泌経路制御タンパク質の探索

    伊藤‌駿, 松下‌明理, 桑田‌啓子, 鄭‌光傑, 高原‌照直, 柴田‌秀樹

    第72回日本細胞生物学会大会     2020.6

  9. Ca<sup>2+</sup>結合タンパク質ALG-2の損傷リソソーム動員機構の解析

    川野‌琢己, 舟橋‌里帆, 高原‌照直, 牧‌正敏, 柴田‌秀樹

    第72回日本細胞生物学会大会     2020.6

  10. 近接依存性標識法を用いた小胞体の輸送小胞出芽部位に局在するタンパク質の網羅的探索

    松下明理, 高原照直, 桑田啓子, 牧正敏, 柴田秀樹

    日本農芸化学会関西・中部支部2019年度合同神戸大会     2019.9

  11. アミノ酸応答性mTORC1制御におけるカルシウムシグナルの意義

    高原照直, 池田奈央, 杉山理紗, 石井千愛, 柴田秀樹, 牧正敏

    日本農芸化学会関西・中部支部2019年度合同神戸大会     2019.9

  12. Ca<sup>2+</sup>結合蛋白質ALG-2の多彩な機能：生体膜を引き込む装置と押し出す装置の調節を中心に Invited

    柴田秀樹

    日本農芸化学会中四国支部第29回若手シンポジウム（第11回農芸化学の未来開拓セミナー）     2019.5

  13. 小胞体のCOPII小胞出芽領域におけるカルシウム・イメージングとカルシウムチャネルの探索

    松下明理, 高橋維朝, 林本敬大, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会大会講演要旨集(Web)   Vol. 2018   page： ROMBUNNO.3A23p02 (WEB ONLY)   2018.3

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    Language：Japanese  

    J-GLOBAL

  14. ストア作動性Ca<sup>2+</sup>流入調節因子SARAFの翻訳後修飾におけるALG‐2の役割

    村松彩夏, ZHANG Wei, 寺西直樹, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会大会講演要旨集(Web)   Vol. 2018   page： ROMBUNNO.3A24a14 (WEB ONLY)   2018.3

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    Language：Japanese  

    J-GLOBAL

  15. アポトーシス促進蛋白質CDIP1に対するALG‐2のカルシウム依存的アダプター機能の解析

    森可奈子, 犬飼隆太, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会大会講演要旨集(Web)   Vol. 2018   page： ROMBUNNO.3A24a13 (WEB ONLY)   2018.3

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    Language：Japanese  

    J-GLOBAL

  16. 微小管結合タンパク質MAP1B内のCa<sup>2+</sup>を介した新規機能領域の同定と解析

    河野雄太, 新居裕美香, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会中部支部例会講演要旨集(Web)   Vol. 180th   page： 33 (WEB ONLY)   2017.10

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    Language：Japanese  

    J-GLOBAL

  17. カルシウムシグナルによる分泌経路の新規制御メカニズム解析

    新居裕美香, 井上国子, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会中部支部例会講演要旨集(Web)   Vol. 180th   page： 32 (WEB ONLY)   2017.10

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    Language：Japanese  

    J-GLOBAL

  18. アネキシンA11とそのALS関連変異体の過剰発現がもたらすカルシウムホメオスタシスへの影響

    林本敬大, 柴田秀樹, 高原照直, 牧正敏

    日本農芸化学会中部支部例会講演要旨集(Web)   Vol. 180th   page： 33 (WEB ONLY)   2017.10

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    Language：Japanese  

    J-GLOBAL

  19. 結合モチーフに基づいたカルシウム結合タンパク質ALG‐2の新規相互作用因子探索と同定

    松尾里奈, ZHANG Wei, 寺西直樹, 高原照直, 柴田秀樹, 牧正敏

    日本農芸化学会大会講演要旨集(Web)   Vol. 2017   page： ROMBUNNO.3A02a10 (WEB ONLY)   2017.3

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    Language：Japanese  

    J-GLOBAL

  20. カルシウム結合タンパク質ALG‐2とアポトーシス促進タンパク質CDIP1とScotinの相互作用

    日本農芸化学会大会講演要旨集(Web)   Vol. 2017   page： ROMBUNNO.2A02p06 (WEB ONLY)   2017.3

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    Language：Japanese  

    J-GLOBAL

  21. アミノ酸は細胞内カルシウム濃度上昇を介してmTORC1経路を活性化する

    高原照直, 中村奈央, WANG Yue, 渡邊穂実, 柴田秀樹, 牧正敏

    日本農芸化学会大会講演要旨集(Web)   Vol. 2017   page： ROMBUNNO.2A02p11 (WEB ONLY)   2017.3

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    Language：Japanese  

    J-GLOBAL

▼display all

To the head of MISC.▲

Presentations 23

  1. ALS原因遺伝子産物TDP-43の定量的解析を目的としたモデル培養細胞の開発

    舟橋里帆、高原照直、牧正敏、柴田秀樹

    日本農芸化学会2022年度（令和4年度）大会  2022.3.17  日本農芸化学会

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    Event date： 2022.3

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：オンライン  

  2. 細胞成長制御を司る mTORC1 経路の新規制御因子の探索と同定

    小林海咲、石井千愛、牧正敏、柴田秀樹、高原照直

    日本農芸化学会中部支部第190回例会  2021.9.18  日本農芸化学会中部支部

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    Event date： 2021.9

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：オンライン  

  3. 動物細胞のアミノ酸応答におけるカルシウムの作用機序の解明

    雨宮優奈、池田奈央、柴田秀樹、牧正敏、高原照直

    日本農芸化学会中部支部第190回例会  2021.9.18  日本農芸化学会中部支部

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    Event date： 2021.9

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：オンライン  

  4. 動物細胞の成長制御を司るmTORC1経路のCa2+シグナルによる調節機構の解析

    雨宮優奈、池田奈央、牧正敏、柴田秀樹、高原照直

    第85回日本生化学会中部支部例会・シンポジウム  2021.5.22  日本生化学会中部支部

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    Event date： 2021.5

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：オンライン  

  5. 損傷リソソームへのCa2+結合タンパク質ALG-2動員の分子機構解析

    川野琢己、舟橋里帆、森花菜子、桑田啓子、牧正敏、高原照直、柴田秀樹

    第43回日本分子生物学会年会  日本分子生物学会

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    Event date： 2020.12

    Language：Japanese   Presentation type：Poster presentation  

    Venue：Web開催  

  6. ストア作動性カルシウム流入制御因子SARAFの二量体形成におけるALG-2の役割

    河原由衣、高原照直、柴田秀樹、牧正敏

    第187回日本農芸化学会中部支部例会  日本農芸化学会中部支部

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    Event date： 2020.9

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：Web開催  

  7. アミノ酸応答シグナル経路におけるカルシウムを介した新規制御機構の解明

    雨宮優奈、池田奈央、柴田秀樹、牧正敏、高原照直

    第187回日本農芸化学会中部支部例会  日本農芸化学会中部支部

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    Event date： 2020.9

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：Web開催  

  8. Ca2+結合タンパク質ALG-2の損傷リソソーム動員機構の解析

    川野琢己、舟橋里帆、高原照直、牧正敏、柴田秀樹

    第72回日本細胞生物学会大会  2020.6  日本細胞生物学会

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    Event date： 2020.6

    Language：Japanese  

    Venue：Web開催  

  9. 近接依存性標識法を用いた初期分泌経路制御タンパク質の探索

    伊藤駿、松下明理、桑田啓子、鄭光傑、高原照直、柴田秀樹

    第72回日本細胞生物学会大会 

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    Event date： 2020.6

    Language：Japanese  

    Venue：Web開催  

  10. カルシウム応答性NFATレポーター測定によるTRPチャネルの機能評価

    阿知波卓也，張維，高原照直，柴田秀樹，牧正敏

    日本農芸化学会2019年度大会 

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    Event date： 2019.3

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：東京農業大学   Country：Japan  

  11. アミノ酸によるmTORC1活性化の新規メカニズムの解析

    高原照直, 池田奈央, 石井千愛, 柴田秀樹, 牧正敏

    日本農芸化学会2019年度大会 

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    Event date： 2019.3

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：東京農業大学   Country：Japan  

  12. リソソーム傷害部位へのカルシウム結合タンパク質ALG-2の動員

    林本敬大, 柴田秀樹, 川野琢己, 高原照直, 牧正敏

    日本農芸化学会2019年度大会 

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    Event date： 2019.3

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：東京農業大学   Country：Japan  

  13. 損傷リソソームへのアネキシンA11とALG-2の動員とその生理的役割の解析

    林本敬大, 川野琢己, 高原照直, 牧正敏, 柴田秀樹

    第4回日本アネキシン研究会年会 

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    Event date： 2018.12

    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：東京大学農学部   Country：Japan  

  14. DNA傷害誘発性アポトーシスにおけるカルシウムイオン結合タンパク質ALG-2のアポトーシス促進性機能の解析

    犬飼隆太、森可奈子、高原照直、柴田秀樹、牧正敏

    第41回日本分子生物学会年会 

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    Event date： 2018.11

    Language：Japanese   Presentation type：Poster presentation  

    Venue：パシフィコ横浜   Country：Japan  

  15. アミノ酸によるmTORC1活性調節におけるカルシウムシグナルの役割の解析

    池田奈央, 石井千愛, 渡邊穂実, 王悦, 中村奈央, 高原照直, 柴田秀樹, 牧正敏

    第41回日本分子生物学会年会 

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    Event date： 2018.11

    Language：Japanese   Presentation type：Poster presentation  

    Country：Japan  

  16. 微小管結合タンパク質MAP1Bを介したアポトーシス誘導経路の解析

    河野雄太、新居裕美香、高原照直、柴田秀樹、牧正敏

    第41回日本分子生物学会年会 

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    Event date： 2018.11

    Language：Japanese   Presentation type：Poster presentation  

    Country：Japan  

  17. SARAFとNedd4 ファミリーE3ユビキチンリガーゼとの相互作用解析

    寺西直樹, 村松彩夏, 張維, 髙原照直, 柴田秀樹, 牧正敏

    第41回日本分子生物学会年会 

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    Event date： 2018.11

    Language：Japanese   Presentation type：Poster presentation  

    Country：Japan  

  18. SARAFのユビキチン修飾におけるALG-2の役割とPPxY配列の関与

    村松彩夏, 張維, 寺西直樹, 河原由衣, 髙原照直, 柴田秀樹, 牧正敏

    第41回日本分子生物学会年会 

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    Event date： 2018.11

    Language：Japanese   Presentation type：Poster presentation  

    Venue：パシフィコ横浜   Country：Japan  

  19. 近接ラベリング手法を用いたコラーゲン分泌制御因子の網羅的探索

    松下明理，柴田秀樹，桑田啓子, 高原照直，牧正敏

    日本農芸化学会第183回中部支部例会 

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    Event date： 2018.9

    Language：Japanese   Presentation type：Poster presentation  

    Country：Japan  

  20. The penta-EF-hand ALG-2 protein interacts with the SOCE regulator SARAF and interferes with ubiquitylation International conference

    Masatoshi Maki, Wei Zhang, Ayaka Muramatsu, Naoki Teranishi, Rio Matsuo, Terunao Takahara, Hideki Shibata

    European Calcium Society 2018 

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    Event date： 2018.9

    Language：English   Presentation type：Poster presentation  

    Venue：Hamburg, Germany   Country：Germany  

  21. Adaptor function of a calcium-binding protein ALG-2 in doxorubicin-induced apoptosis

    Kanako Mori, Ryuta Inukai, Terunao Takahara, Masatoshi, Maki, Hideki Shibata

    Joint Annual Meeting of JSCB 51st and JSCB 70th 

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    Event date： 2018.6

    Language：English   Presentation type：Poster presentation  

    Country：Japan  

  22. 小胞体からのタンパク質の搬出におけるカルシウム結合タンパク質の生理的役割

    京卓志、横山健、山室南、三宅博、牧正敏、柴田秀樹

    日本農芸化学会中部支部　第165回例会 

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    Event date： 2012.10

    Language：Japanese   Presentation type：Poster presentation  

    Country：Japan  

  23. The penta-EF-hand protein ALG-2 stabilises a COPII component Sec31A at ER exit sites by recruiting Annexin A11 International conference

    Hideki Shibata, Takashi Kanadome, Minami Yamamuro, Stephen E. Moss, Masatoshi Maki

    12th symposium of the European Calcium Society 

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    Event date： 2012.9

    Language：English   Presentation type：Oral presentation (general)  

    Country：France  

▼display all

To the head of Presentations.▲

Research Project for Joint Research, Competitive Funding, etc. 4

  1. 線維性コラーゲンの分泌機構の解明とその制御を目指す基礎研究

    2021.2

    公益財団法人　小柳財団  2021年度研究助成 

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\1000000

  2. カルシウム依存性ユビキチン化修飾を介するコラーゲン分泌調節機構に関する研究

    2018.4 - 2020.3

    堀科学芸術振興財団 

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    Authorship：Principal investigator  Grant type：Competitive

  3. カルシウム振動による物質輸送制御機構の解析

    2011.11 - 2013.10

    豊秋奨学会　研究費助成 

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    Authorship：Principal investigator  Grant type：Competitive

  4. カルシウム振動のシグナル変換機構の解明

    2009

    上原記念生命科学財団 

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    Authorship：Principal investigator  Grant type：Competitive

To the head of Research Project for Joint Research, Competitive Funding, etc..▲

KAKENHI (Grants-in-Aid for Scientific Research) 10

  1. カルシウム結合蛋白質を介するリソソーム膜の損傷応答機構の分子基盤解明

    Grant number：22H02302  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    柴田 秀樹

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    Authorship：Principal investigator 

    Grant amount：\17680000 （ Direct Cost: \13600000 、 Indirect Cost：\4080000 ）

    損傷したリソソームからは加水分解酵素や水素イオン、カルシウムイオンなどが漏出するため、細胞は損傷リソソームの迅速な修復および修復不能な損傷リソソームの除去とリソソームの再生機能を有する。しかし、これらの細胞応答を惹起する分子メカニズムの全容は明らかとされていない。本研究では、損傷リソソームから漏出するカルシウムイオンに応答し、損傷部位に動員されるカルシウム結合蛋白質に着目し、それらと協調して機能する蛋白質の同定とリソソーム損傷を起点とする細胞応答における役割の解明を目指す。本研究成果は、リソソーム損傷を原因とする疾患の発症予防と病態進行緩和の創薬シーズの発見につながることが期待される。
    リソソームは細胞内消化を担う膜で覆われた細胞小器官である。限界膜が損傷したリソソームからは、加水分解酵素や水素イオン、カルシウムイオンなどが漏出する。研究代表者らは、損傷したリソソームにカルシウム結合蛋白質ALG-2が動員される現象を見出しており、リソソームの損傷を誘発した細胞においてALG-2の近傍に存在する蛋白質を同定している。本年度は、その中でLIP5に着目し以下を解析した。
    (1) LIP5の免疫染色実験により、LIP5がリソソーム損傷を誘導した細胞でリソソームに動員されることを観察した。LIP5のリソソーム動員におけるカルシウムイオンの役割を明らかにする目的で、カルシウムキレータであるBAPTA-AMを処理したところ、LIP5のリソソーム動員が抑制された。一方、ALG-2のノックアウト細胞でもリソソーム損傷刺激後のLIP5のリソソーム局在が観察された。
    (2) LIP5の発現抑制がその相互作用蛋白質であるVPS4A/Bの損傷リソソームへの局在に与える影響を解析した。VPS4A/Bはリソソーム損傷刺激を加えた細胞においてリソソームに局在したが、LIP5を発現抑制するとリソソーム局在が観察されなかった。
    (3)LIP5発現抑制細胞のリソソーム損傷刺激後の細胞死誘導に関して、ウエスタンブロット解析により発現抑制していない細胞と比較した。その結果、LIP5の発現抑制細胞はリソソーム損傷刺激後にカスパーゼ3/7の基質蛋白質の切断断片が多く検出され、アポトーシスが誘導されていると考えられた。
    リソソーム損傷を誘発した細胞においてALG-2の近傍蛋白質として同定された蛋白質が、カルシウム依存的に損傷リソソームに局在することを明らかにし、国内学会で発表できる成果が得られた。
    LIP5を含めALG-2近傍蛋白質として同定した蛋白質の多くは、カルシウム依存的に損傷リソソームに動員されるものの、ALG-2ノックアウト細胞でもリソソームに動員されることから、ALG-2以外のカルシウム結合蛋白質の関与が予想される。損傷リソソームへの動員が報告されている、また予想されるカルシウム結合蛋白質の発現抑制や阻害剤の添加がLIP5などの損傷リソソーム動員に与える影響を解析する。また、LIP5のリソソーム損傷応答における役割の解明を進める。さらに、筋萎縮性側索硬化症の発症に関連するカルシウム結合蛋白質の変異体の発現がリソソーム損傷応答に与える影響を解析する。

  2. Functional modification of the endosomal pathway to inhibit neurodegenerative processes.

    Grant number：19K22275  2019.6 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    SHIBATA Hideki

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\6240000 （ Direct Cost: \4800000 、 Indirect Cost：\1440000 ）

    A characteristic lesion of neurodegenerative diseases is the formation of amyloid fiber-like aggregates, exemplified by TDP-43 in amyotrophic lateral sclerosis (ALS). Aggregates are formed when pathological proteins are seeded and sequester normal cytoplasmic proteins. In this study, cell lines were established that can be monitored the formation of aggregates in the cytoplasm by the ALS-associated mutants of annexin A11 and TDP-43 with mutations in its nuclear localization signal and RNA-binding motifs. Using these cells, the mutant proteins were found to form aggregates triggered by lysosomal damage. On the other hand, these mutants were shown to be rapidly degraded by proteasomes in cells where they did not form aggregates.

  3. A study of a calcium-binding protein-regulated network in collagen secretion

    Grant number：18H02135  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Shibata Hideki

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\17420000 （ Direct Cost: \13400000 、 Indirect Cost：\4020000 ）

    Collagens are structural proteins that constitute approximately 25% of human dry body weight and are secreted from the endoplasmic reticulum to the extracellular space via the Golgi apparatus. In this study, we aimed to elucidate the molecular mechanisms by which calcium-responsive regulators, mainly the calcium-binding protein ALG-2, control export of collagens from the endoplasmic reticulum, by searching for target molecules of ALG-2 by its binding motifs and by using proximity-dependent labeling methods coupled with mass spectrometry. The protein-protein interaction networks and subcellular localization of multiple candidate regulators and their functions were elucidated by biochemical and molecular cell biological approaches.

  4. Elucidation of physiological functions of the EF-hand protein ALG-2 as a calcium-stress response factor

    Grant number：17H03803  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    MAKI Masatoshi

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    Authorship：Coinvestigator(s) 

    Ca2+ is a signaling molecule that plays important roles in eukaryotic cells.In order to investigate the physiological functions of Ca2+-binding protein ALG-2, we searched and identified four new ALG-2-interacting proteins.MISSL accumulates at endoplasmic reticulum (ER) exit sites with ALG-2 upon increase in cytosolic Ca2+ concentrations. It cooperates with microtubule associated protein 1B (MAP1B) to regulate vesicular transport of cargoes from the ER to the Golgi apparatus. ALG-2 binds single-pass ER transmembrane protein named SARAF and suppresses ubiquitination of SARAF. CDIP1 localizes at the endomembrane systems and binds a subset of ESCRT-I proteins in the presence of Ca2+/ALG-2 to promote cell death. We analyzed recruitment of ALG-2 to lysosomes upon impairment of lysosomal membranes. We established a new high sensitive Ca2+-response reporter gene assay system to monitor effects of Ca2+. The system is expected to apply to evaluate food constituents and drugs.

  5. Elucidation and application of regulatory mechanisms underlying biogenesis of transport vesicles budding from the endoplasmic reticulum

    Grant number：15K07384  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Shibata Hideki, MAKI Masatoshi, TAKAHARA Terunao, KUWATA Keiko, KANADOME Takashi, SATO Akane, INOUE Kuniko, ARAI Yumika, KONO Yuta

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    Authorship：Principal investigator 

    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    In mammalian cells, proteins destined for secretion are transported from specialized region of the ER, called ER exit site (ERES), by COPII vesicles. The aim of this study was to investigate the role of ALG-2, a calcium-binding protein, in the regulation of COPII-mediated protein transport. ALG-2 directly interacts with Sec31A, an outer coat component of COPII. Firstly, we identified Trk-fused gene (TFG) product as a novel target for ALG-2. Overexpression of ALG-2 enhanced the localization of TFG to the ERES. Secondly, MISSL was shown to be recruited to the ERES by ALG-2 in response to calcium mobilization. We also found that ALG-2 bridged between MISSL and MAP1B. In our co-immunoprecipitation analysis, TFG, MISSL and MAP1B did not form the complex with Sec31A, suggesting that ALG-2 may have divergent functions at the ERES. Finally, we reported that amyotrophic lateral sclerosis (ALS)-associated mutations in annexin A11 caused abnonormality in binding to S100A6.

  6. Analysis of cellular signal transduction by amino acids via intracellular Ca2+ rise

    Grant number：15K18680  2015.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

    Takahara Terunao, MAKI Masatoshi, SHIBATA Hideki

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    In this study, we sought to clarify the role of Ca2+ in the cellular mechanism of amino acids sensing and the cellular response. Addition of amino acids to the amino acid-starved cell induces the Ca2+ entry from extracellular space, leading to the increase of intracellular Ca2+ concentration. By using the several inhibitors that target particular Ca2+ channels, we identified that Amiloride-sensitive Ca2+ channel appears to responsible for the Ca2+ entry. In addition, we also investigated how increased Ca2+ levels affect the mTORC1, which is a central regulator of amino acid sensing pathway. It is known that amino acids activate mTORC1 via two distinct small GTPases, called Rag GTPases and Rheb GTPase. We found that the action of Rheb GTPase but not Rag was affected by Ca2+. These results suggest a novel regulatory mechanism of mTORC1 through the change of intracellular Ca2+ concentration in response to amino acids.

  7. Mechanism of calcium-response regulation of EF-hand protein ALG-2 in the nucleus and membranes

    Grant number：26292050  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Maki Masatoshi, TAKAHARA Terunao, WAKATSUKI Soichi, KAWASAKI Masato, SUZUKI Hironori, SASAKI Kanae, TAKAHASHI Takeshi, KANADOME Takashi, ZHANG Wei, KOJIMA Kyosuke, MATSUO Rina

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    In the early secretory pathway of proteins from the endoplasmic reticulum to the Golgi apparatus, Ca2+-dependent accumulation of ALG-2 to the endoplasmic reticulum exit sites bridges Sec31A, a component of COPII outer shell, and annexin A11 and retards transport of a model cargo membrane protein, and causes multimerization of the TFG protein. Refinement of the binding sequences by the X-ray crystal structural analysis of ALG-2 and the Sec31A peptide and by mutational analysis of both proteins, we propose a new ALG-2-binding motif. We searched proteins containing the motif and found a novel ALG-2 interacting proteins that passes through the ER membrane. ALG-2 was found to inhibit the activity of the Ca2+-dependent transcription factor NFAT.

  8. 初期分泌経路におけるカルシウム振動シグナル変換機構の解析

    2012.4 - 2015.3

    科学研究費補助金  基盤研究(C)

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    Authorship：Principal investigator 

  9. カルシウム結合タンパク質ALG-2による小胞体からの輸送小胞出芽の制御機構の解析

    2009.4 - 2011.3

    科学研究費補助金  若手研究(B)

    柴田　秀樹

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    Authorship：Principal investigator 

  10. カルシウム結合タンパク質ＡＬＧ－２による小胞体－ゴルジ体間小胞輸送制御機構の解明

    2007

    科学研究費補助金  若手研究（Ｂ），課題番号：19770107

    柴田　秀樹

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    Authorship：Principal investigator 

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To the head of KAKENHI (Grants-in-Aid for Scientific Research).▲
 

Teaching Experience (On-campus) 8

  1. 応用生命科学実験実習2

    2020

  2. 遺伝子の世界

    2020

  3. Basics of Bioagricultural Sciences

    2018

  4. 分子細胞生物学特論１

    2018

  5. 応用生命科学実験実習２

    2018

  6. 遺伝子の世界

    2018

  7. 細胞生物学３

    2018

  8. 分子細胞生物学１

    2018

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To the head of Teaching Experience (On-campus).▲