研究者詳細 - 髙原　照直

論文 - 髙原　照直

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Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding Open Access

Amemiya, Y; Ioi, Y; Araki, M; Kontani, K; Maki, M; Shibata, H; Takahara, T

JOURNAL OF BIOLOGICAL CHEMISTRY 301 巻 ( 2 ) 頁： 108122 2025年2月

記述言語：英語出版者・発行元：Journal of Biological Chemistry

The mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca2+) concentration modulates the mTORC1 pathway via binding of the Ca2+ sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca2+/CaM modulates mTORC1 activity remains unclear. Here, we performed a binding assay based on nano-luciferase reconstitution, a method for detecting weak interactions between TSC2 and its target, Ras homolog enriched in the brain (Rheb), an activator of mTORC1. CaM inhibited the binding of TSC2 to Rheb in a Ca2+-dependent manner. Live-cell imaging analysis indicated increased interaction between the CaM-binding region of TSC2 and CaM in response to elevated intracellular Ca2+ levels. Furthermore, treatment with carbachol, an acetylcholine analog, elevated intracellular Ca2+ levels and activated mTORC1. Notably, carbachol-induced activation of mTORC1 was inhibited by CaM inhibitors, corroborating the role of Ca2+/CaM in promoting the mTORC1 pathway. Consistent with the effect of Ca2+/CaM on the TSC2-Rheb interaction, increased intracellular Ca2+ concentration promoted the dissociation of TSC2 from lysosomes without affecting Akt-dependent phosphorylation of TSC2, suggesting that the regulatory mechanism of TSC2 by Ca2+/CaM is distinct from the previously established action mechanism of TSC2. Collectively, our findings offer mechanistic insights into TSC2-Rheb regulation mediated by Ca2+/CaM, which links Ca2+ signaling to mTORC1 activation.

DOI： 10.1016/j.jbc.2024.108122

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells

Inukai, R; Mori, K; Maki, M; Takahara, T; Shibata, H

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 25 巻 ( 12 ) 2024年6月

New Insights into the Regulation of mTOR Signaling via Ca(2+)-Binding Proteins. 査読有り

Amemiya Y, Maki M, Shibata H, Takahara T

International journal of molecular sciences 24 巻 ( 4 ) 2023年2月

Roles of phosphatidylserine and phospholipase C in the activation of TOR complex 2 signaling in Saccharomyces cerevisiae. 査読有り

Nomura W, Ng SP, Takahara T, Maeda T, Kawada T, Goto T, Inoue Y

Journal of cell science 135 巻 ( 17 ) 2022年9月

Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin 査読有り

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

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 22 巻 ( 13 ) 2021年7月

The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B 査読有り

Inukai Ryuta, Mori Kanako, Kuwata Keiko, Suzuki Chihiro, Maki Masatoshi, Takahara Terunao, Shibata Hideki

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 22 巻 ( 3 ) 2021年2月

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

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

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 21 巻 ( 17 ) 2020年9月

Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes 招待有り査読有り

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

JOURNAL OF BIOMEDICAL SCIENCE 27 巻 ( 1 ) 頁： 87 2020年8月

High Sensitive Quantitative Binding Assays Using a Nanoluciferase-Fused Probe for Analysis of ALG-2-Interacting Proteins

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

CALCIUM-BINDING PROTEINS OF THE EF-HAND SUPERFAMILY 1929 巻頁： 501 - 516 2019年

Cellular Ca2+-Responding Nanoluciferase Reporter Gene System Directed by Tandemly Repeated Pseudo-palindromic NFAT-Response Elements

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

CALCIUM-BINDING PROTEINS OF THE EF-HAND SUPERFAMILY 1929 巻頁： 95 - 109 2019年

A microtubule-associated protein MAP1B binds to and regulates localization of a calcium-binding protein ALG-2 査読有り

Takahara, T; Arai, Y; Kono, Y; Shibata, H; Maki, M

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 497 巻 ( 2 ) 頁： 492 - 498 2018年3月

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

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

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 19 巻 ( 2 ) 2018年2月

The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins. 査読有り

Takahara T, Inoue K, Arai Y, Kuwata K, Shibata H, Maki M.

J. Biol. Chem. 292 巻頁： 17057-17072 2017年10月

The calcium-binding protein ALG-2 promotes endoplasmic reticulum exit site localization and polymerization of Trk-fused gene (TFG) protein. 査読有り

Kanadome T, Shibata H, Kuwata K, Takahara T, Maki M.

FEBS J. 284 巻 ( 1 ) 頁： 56-76 2017年1月

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

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

FEBS JOURNAL 284 巻 ( 1 ) 頁： 56-76 2017年1月

Multifaceted Roles of ALG-2 in Ca(2+)-Regulated Membrane Trafficking. 査読有り

Masatoshi Maki, Terunao Takahara, Hideki Shibata

Int. J. Mol. Sci. 17 巻 ( 9 ) 頁： E1401 (1-23) 2016年8月

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. 査読有り

Akira Inokawa, Tatsuyoshi Inuzukam Terunao Takahara, Hideki Shibata, and Masatoshi Maki

Bioscience Reports 36 巻頁： e00287 2016年

Structural Analysis of the Complex between Penta-EF-Hand ALG-2 Protein and Sec31A Peptide Reveals a Novel Target Recognition Mechanism of ALG-2 査読有り

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

International Journal of Molecular Sciences 16 巻頁： 3677-3699 2015年2月

Involvement of calpain-7 in epidermal growth factor receptor degradation via the endosomal sorting pathway. 査読有り

Maemoto, Y., Ono, Y., Kiso, S., Shibata, H., Takahara, T., Sorimachi, H., and Maki, M.

FEBS Journal 281 巻頁： 3642-3655 2014年

Evolutionary conserved regulation of TOR signaling. 招待有り査読有り

Terunao Takahara, Tatsuya Maeda

Journal of Biochemistry 154 巻頁： 1-10 2013年

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