インスリン受容体基質のモノユビキチン化を介したインスリン活性調節機構の解明

• 研究課題/領域番号: 24790928
• 研究種目: 若手研究(B)
• 配分区分: 基金
• 研究分野: 代謝学
• 研究機関: 広島大学
• 研究代表者: 福嶋 俊明 広島大学, 医歯薬保健学研究院, 助教 (70543552)
• 研究期間 (年度): 2012-04-01 – 2015-03-31
• 研究課題ステータス: 完了 (2014年度)
• 配分額: 4,160千円 (直接経費: 3,200千円、間接経費: 960千円); 2013年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円); 2012年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: インスリン / インスリン様成長因子 / インスリン受容体基質 / 糖尿病 / ユビキチン / 細胞内シグナル / Nedd4 / Epsin1 / 細胞内シグナル伝達 / 国際情報交換 スウェーデン

研究成果の概要

インスリンとインスリン様成長因子(IGF)は互いに類似した構造のホルモンで、インスリンは血糖値の調節に、IGFは細胞増殖や個体成長に重要な役割を果たします。私達は、これまでにインスリンやIGFの細胞内情報伝達を担うタンパク質の一つ「インスリン受容体基質」がモノユビキチン化という種類の分子修飾を受けるとインスリンやIGFの作用が強まることを見つけており、今回の研究によってその詳細な分子機構を明らかにすることが出来ました。また、肝臓では細胞が受け取る栄養量が変化すると、この新しい機構を介してインスリンへの応答性が変化することも明らかになり、糖尿病発症機構の理解にとっても重要な発見と考えられました。

研究成果

• [雑誌論文] Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model. (2015)
  • 著者名/発表者名: Hirofumi Okubo, Yusuke Nakatsu, Hideyuki Sakoda, Akifumi Kushiyama, Midori Fujishiro, Toshiaki Fukushima, Yasuka Matsunaga, Haruya Ohno, Masayasu Yoneda, Hideaki Kamata, Takanori Shinjo, Misaki Iwashita, Fusanori Nishimura, and Tomoichiro Asano
  • 雑誌名: Am. J. Physiol. Gastrointest. Liver Physiol. 巻: 308 号: 2 ページ: 151-158
  • DOI: 10.1152/ajpgi.00198.2014
  • 査読あり
• [雑誌論文] Nedd4-induced mono-ubiquitination of IRS-2 enhances IGF signaling and mitogenic activity. (2015)
  • 著者名/発表者名: Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Jing Luan, Cunming Duan, Yasushi Saeki, Keiji Tanaka, Shun-Ichiro Iemura, TohruNatsume, Kazuhiro Chida, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • 雑誌名: Nature communications 巻: 6 号: 1 ページ: 6780-6780
  • DOI: 10.1038/ncomms7780
  • NAID: 120006348510
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• [雑誌論文] Insulin receptor substrate-1 associates with small nucleolar RNA which contributes to ribosome biogenesis. (2014)
  • 著者名/発表者名: Ozoe A, Sone M, Fukushima T, Kataoka N, Chida K, Asano T, Hakuno F, Takahashi S-I.
  • 雑誌名: Frontiers in Endocrinology 巻: 5 ページ: 24-24
  • DOI: 10.3389/fendo.2014.00024
  • 査読あり / オープンアクセス
• [雑誌論文] Familial short stature is associated with a novel dominant-negative heterozygous insulin-like growth factor 1 receptor (IGF1R) mutation (2014)
  • 著者名/発表者名: Kawashima Y, Hakuno F, Okada SI, Hotsubo T, Kinoshita T, Fujimoto M, Nishimura R, Fukushima T, Hanaki K, Takahashi SI, Kanzaki S
  • 雑誌名: Clinical Endocrinology (Oxf) 巻: Epub ahead of print 号: 2 ページ: 1-3
  • DOI: 10.1111/cen.12317
  • 査読あり
• [雑誌論文] Lactobacillus casei strain Shirota protects against non-alcoholic steatohepatitis development in a rodent model (2013)
  • 著者名/発表者名: Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, Matsunaga Y, Kamata H, Asahara T, Yoshida Y, Chonan O, Iwashita M, Nishimura F, Asano T
  • 雑誌名: American Journal Physiolgy-Gastrointestinal and Liver Physiogy 巻: 305 号: 12 ページ: 911-918
  • DOI: 10.1152/ajpgi.00225.2013
  • 査読あり
• [雑誌論文] Insulin Receptor Substrate-1 (IRS-1) Forms a Ribonucleoprotein Complex Associated with Polysomes (2013)
  • 著者名/発表者名: Ozoe A, Sone M, Fukushima T, Kataoka N, Arai T, Chida K, Asano T, Hakuno F, Takahashi S-I
  • 雑誌名: FEBS Lett. 巻: 587(15) 号: 15 ページ: 2319-24
  • DOI: 10.1016/j.febslet.2013.05.066
  • 査読あり
• [雑誌論文] Par14 associates with IRS-1, thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions. (2013)
  • 著者名/発表者名: Zhang J, Nakatsu Y, Sinjo T, Guo Y, Sakoda H, Yamamotoya T, Otani Y, Okubo H, Kushiyama A, Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H, Nishimura F, Katagiri H, Takahashi SI, Kurihara H, Uchida T, Asano T.
  • 雑誌名: Ｊournal of Biological Chemistry 巻: 288 号: 28 ページ: 20692-20701
  • DOI: 10.1074/jbc.m113.485730
  • 査読あり
• [雑誌論文] Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development. (2013)
  • 著者名/発表者名: Kushiyama A, Sakoda H, Oue N, Okubo M, Nakatsu Y, Ono H, Fukushima T, Kamata H, Nishimura F, Kikuchi T, Fujishiro M, Nishiyama K, Aburatani H, Kushiyama S, Iizuka M, Taki N, Encinas J, Sentani K, Ogonuki N, Ogura A, Kawazu S, Yasui W, Higashi Y, Kurihara H, Katagiri H, Asano T.
  • 雑誌名: Arteriosclerosis, Thrombosis, and Vascular Biology 巻: 33 号: 8 ページ: 1986-1993
  • DOI: 10.1161/atvbaha.113.301546
  • 査読あり / オープンアクセス
• [雑誌論文] インスリン様活性と高齢化社会で克服すべき疾病 (2013)
  • 著者名/発表者名: 高橋伸一郎、伯野史彦、亀井宏泰、Leonard Girnita、Ignacio Torres-Aleman、 東祐輔、福嶋俊明、柴野卓志、尾添淳文、山中大介
  • 雑誌名: 化学と生物 巻: 51(6)
  • NAID: 10031177626
• [雑誌論文] Valsartan Restores Inflammatory Response by Macrophages in Adipose and Hepatic Tissues of LPS-infused Mice. (2013)
  • 著者名/発表者名: Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima T, Kumamoto S, Kamata H, Nishimura F, Asano T.
  • 雑誌名: Adipocyte 巻: 未定
  • 査読あり
• [雑誌論文] Integrator complex plays anessential role inadipose differentiation (2013)
  • 著者名/発表者名: Otani Y, Nakatsu Y, Sakoda H, Fukushima T, Fujishiro M, Kushiyama A, Okubo H, Tsuchiya Y, Ohno H, Takahashi S, Nishimura F, Kamata H, Katagiri H, Asano T.
  • 雑誌名: Biochemical and Biophysical Research Communications 巻: 434 号: 2 ページ: 197-202
  • DOI: 10.1016/j.bbrc.2013.03.029
  • 査読あり
• [雑誌論文] Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. (2012)
  • 著者名/発表者名: Iwashita M, Sakoda H, Kushiyama A, Fujishiro M, Ohno H, Nakatsu Y, Fukushima T, Kumamoto S, Tsuchiya Y, Kikuchi T, Kurihara H, Akazawa H, Komuro I, Kamata H, Nishimura F, Asano T.
  • 雑誌名: American Journal of Physiology - Endocrinology and Metabolism 巻: 302 号: 3 ページ: 286-296
  • DOI: 10.1152/ajpendo.00324.2011
  • 査読あり
• [雑誌論文] Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and atherosclerosis development (2012)
  • 著者名/発表者名: Kushiyama A, Okubo H, Sakoda H, Kikuchi T, Fujishiro M, Sato H, Kushiyama S, Iwashita M, Nishimura F, Fukushima T, Nakatsu Y, Kamata H, Kawazu S, Higashi Y, Kurihara H, Asano T.
  • 雑誌名: Arterioscler Thromb Vasc Biol 巻: 32 号: 2 ページ: 291-298
  • DOI: 10.1161/atvbaha.111.234559
  • 査読あり
• [雑誌論文] Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation (2012)
  • 著者名/発表者名: Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi JI, Hanaki K, Nanba E, Takahashi SI, Kanzaki S
  • 雑誌名: Clin.Endocrinol. 巻: (in press) 号: 2 ページ: 246-54
  • DOI: 10.1111/j.1365-2265.2012.04357.x
  • 査読あり
• [雑誌論文] Phosphatidylinositol 3-kinase-binding protein, PI3KAP/XB130, is required for cAMP-induced amplification of IGF mitogenic activity in FRTL-5 thyroid cells (2012)
  • 著者名/発表者名: Yamanaka D, Akama T, Fukushima T, Nedachi T, Kawasaki C, Chida K, Minami S, Suzuki K, Hakuno F, Takahashi S-I.
  • 雑誌名: Mol Endocrinol 巻: 26 号: 6 ページ: 1043
  • DOI: 10.1210/me.2011-1349
  • 査読あり
• [雑誌論文] Insulin/insulin-like growth factor (IGF) stimulation abrogates an association between a deubiquitinating enzyme USP7 and insulin receptor substrates (IRSs) followed by proteasomal degradation of IRSs (2012)
  • 著者名/発表者名: Yoshihara H, Fukushima T, Hakuno F, Saeki Y, Tanaka K, Ito A, Yoshida M, Iemura S, Natsume T, Asano T, Chida K, Girnita L, Takahashi S-I
  • 雑誌名: Biochem. Biophys. Res. Commun. 巻: 423 号: 1 ページ: 122-127
  • DOI: 10.1016/j.bbrc.2012.05.093
  • 査読あり
• [雑誌論文] Phosphatidylinsitol 3-kinase (PI3K) activity bound to insulin-like growth factor-I (IGF-I) receptor, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation. (2012)
  • 著者名/発表者名: Fukushima T, Nakamura Y, Yamanaka D, Shibano T, Chida K, Minami S, Asano T, Hakuno F, Takahashi S-I.
  • 雑誌名: J. Biol. Chem. 巻: 287 号: 35 ページ: 29713-29721
  • DOI: 10.1074/jbc.m112.393074
  • 査読あり
• [雑誌論文] Role of Pin1 in the pathogenesis of non-alcoholic steatohepatitis in a rodent model (2012)
  • 著者名/発表者名: Nakatsu Y, Otani Y, Sakoda H, Zhang J, Guo Y, Okubo H, Kushiyama A, Fujishiro M, Kikuchi T, Fukushima T, Ohno H, Tsuchiya Y, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Takahashi SI, Kurihara H, Uchida T, Asano T
  • 雑誌名: J Biol Chem 巻: 287 号: 53 ページ: 44526-44535
  • DOI: 10.1074/jbc.m112.397133
  • 査読あり
• [学会発表] The deubiquitinating enzyme, USP9X positively regulates IGF-I-dependent cell growth by inhibition of degradation of insulin receptor substrate (IRS)-2 in cancer cells (2015)
  • 著者名/発表者名: Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Tomoichio Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • 学会等名: Gordon Research Conference: IGF and Insulin System in Physiology and disease
  • 発表場所: Ventura, USA
  • 年月日: 2015-03-08 – 2015-03-13
• [学会発表] Molecular mechanisms by which ubiquitin ligase Nedd4 enhances IRS-2-mediated IGF signaling (2014)
  • 著者名/発表者名: Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Shin-Ichiro Takahashi, Tomoichiro Asano
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan
  • 発表場所: 神戸
  • 年月日: 2014-11-25 – 2014-11-27
• [学会発表] Xanthine oxidase inhibitor febuxostat improves nonalcoholic steatohepatitis (2014)
  • 著者名/発表者名: Yasuka Matsunaga, Yusuke Nakatsu, Yasuyuki Seno, Aya Katasako, Ryuhei Kanaokam Toshiaki Fukushima, Hideaki Kamata, Tomoichiro Asano
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan
  • 発表場所: 神戸
  • 年月日: 2014-11-25 – 2014-11-27
• [学会発表] Roles of prolyl isomerase Pin1 in pancreatic beta cell function (2014)
  • 著者名/発表者名: Yusuke Nakatsu, Keiichi Mori, Yasuka Matsunaga, Toshiaki Fukushima, Hideaki Kamata, Ken Yamaguchi, Hisamitsu Ishihara, Tomoichiro Asano
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan
  • 発表場所: 神戸
  • 年月日: 2014-11-25 – 2014-11-27
• [学会発表] Novel Mechanisms by which Nedd4-IRS-2 Complexes Enhance IGF-I signals, and their Roles in IGF-I Action in Prostate Cancer Cell Proliferation (2014)
  • 著者名/発表者名: Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • 学会等名: The International Congress of the GRS and the IGF Society
  • 発表場所: Singapore
  • 年月日: 2014-10-15 – 2014-10-18
• [学会発表] The deubiquitinating enzyme, USP9X positively regulates insulin-like growth factor (IGF)-dependent cell growth by inhibition of degradation of IGF-I receptor (IGF-IR) and insulin receptor substrate (IRS)-2 in cancer cells (2014)
  • 著者名/発表者名: Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yasushi Saeki, Akihiro Ito, Claire Worrall, Leonard Girnita, Keiji Tanaka, Minoru Yoshida, Tomoichio Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • 学会等名: The International Congress of the GRS and the IGF Society
  • 発表場所: Singapore
  • 年月日: 2014-10-15 – 2014-10-18
• [学会発表] Novel Mechanisms by which Nedd4-IRS-2 complexes enhance IGF-I signals, and their roles in IGF-I action in prostate cancer cell proliferation (2014)
  • 著者名/発表者名: Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • 学会等名: The 7h International Congress of the GRS and the IGF Society
  • 発表場所: Singapore
• [学会発表] インスリン受容体RNAの選択的スプライシングの新しい制御機構 (2014)
  • 著者名/発表者名: Yuka Narita, Atsufumi Ozoe, Toshiaki Fukushima, Naoyuki Kataoka, Akihiro Ito, Minoru Yoshida, Tomoichiro Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • 学会等名: Japan Endocrine Society's Annual Meeting
  • 発表場所: 福岡
• [学会発表] Nedd4-IRS2 complex: mechanisms of the complex formation and its roles in prostate cancer cell proliferation (2013)
  • 著者名/発表者名: Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Kazuhiro Chida, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Yusuke Nakatsu, Hideaki Kamata, Shin-Ichiro Takahashi, Tomoichio Asano
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan
  • 発表場所: 神戸
• [学会発表] The deubiquitinating enzyme, USP9X positively regulates insulin-like growth factor (IGF)-dependent cell growth by inhibition of degradation of IGF-I receptor (IGF-IR) and insulin receptor substrate (IRS)-2 in cancer cells (2013)
  • 著者名/発表者名: Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Tomoichio Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan
  • 発表場所: 神戸
• [学会発表] Ubiquitin-conjugation to IRS by ubiquitin ligase Nedd4 drives Insulin/IGF signaling. (2013)
  • 著者名/発表者名: Toshiaki Fukushima
  • 学会等名: Core-to-Core Project sponsored by JSPS (FY2012-FY2017) INTERNATIONAL OPEN WORKSHOP
  • 発表場所: Stockholm (スウェーデン)
  • 招待講演
• [学会発表] PGAM5, a mitochondrial protein phosphatase, regulates the serine/threonine phosphorylation status and stability of insulin receptor substrates. (2013)
  • 著者名/発表者名: Yosuke Yoneyama, Junichi Inobe, Yukako Kida, Toshiaki Fukushima, Shiori Sekine, Tomoichiro Asano, Kazuhiro Chida, Kohsuke Takeda, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • 学会等名: Annual Meeting of the Molecular Biology Society of Japan,
  • 発表場所: 神戸
• [学会発表] Nedd4 potentiates IRS-2-mediated insulin/IGF signals and bioactivities. (2012)
  • 著者名/発表者名: Fukushima T, Yoshihara H, Hakuno F, Saeki Y, Tanaka K, Ito A, Yoshida M, Nakatsu Y, Sakoda H, Kamata H, Takahashi SI, Asano T
  • 学会等名: Annual Meeting of the Japan Diabetes Society
  • 発表場所: 横浜
• [学会発表] Ubiquitin ligase Nedd4 interacts with insulin receptor substrate (IRS)-2 in response to humoral/nutritional stimuli, thereby enhancing IRS-2-mediated IGF/insulin signals through a novel mechanism. (2012)
  • 著者名/発表者名: Fukushima T, Yoshihara H, Hakuno F, Saeki Y, Tanaka K, Ito A, Yoshida M, Chida K, Sakoda H, Asano T, Takahashi SI.
  • 学会等名: The 6th International Congress of the GRS and the IGF Society
  • 発表場所: ドイツ ミュンヘン
• [備考] 広島大学大学院医歯薬学総合研究科 創生医科学専攻探索医科学講座 医化学研究室
  • URL: http://home.hiroshima-u.ac.jp/ikagaku/
• [備考] 広島大学大学院医歯薬学総合研究科創生医科学専攻探索医科学講座医化学研究室
  • URL: http://home.hiroshima-u.ac.jp/ikagaku/