Novel regulatory mechanism of insulin activity through IRS monoubiquitination

• Project/Area Number: 24790928
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Hiroshima University
• Principal Investigator: FUKUSHIMA Toshiaki 広島大学, 医歯薬保健学研究院, 助教 (70543552)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 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

Outline of Final Research Achievements

Insulin is a hormone that regulates blood glucose levels. Insulin-like growth factor (IGF) is another hormone similar in molecular structure to insulin, and IGF promotes cell proliferation and body growth. We previously found that insulin receptor substrate (IRS), a protein that mediates insulin/IGF intracellular signaling, is functionally changed by its modification called as "monoubiquitination", and it leads to the enhancement of insulin/IGF signaling and induction of their bioactivities. In this study, we elucidated the detailed molecular mechanisms underlying the enhancement of insulin/IGF signaling by IRS monoubiquitination. Furthermore, we found that, when the amounts of nutrition given to hepatocytes are changed, hepatic insulin sensitivity also changed through this novel mechanism. This finding is thought to be important for understanding pathogenic mechanism of diabetes.

Research Products

• [Journal Article] Mosapride citrate improves nonalcoholic steatohepatitis with increased fecal lactic acid bacteria and plasma glucagon-like peptide-1 level in a rodent model. (2015)
  • Author(s): 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
  • Journal Title: Am. J. Physiol. Gastrointest. Liver Physiol. Volume: 308 Issue: 2 Pages: 151-158
  • DOI: 10.1152/ajpgi.00198.2014
  • Peer Reviewed
• [Journal Article] Nedd4-induced mono-ubiquitination of IRS-2 enhances IGF signaling and mitogenic activity. (2015)
  • Author(s): 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
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 6780-6780
  • DOI: 10.1038/ncomms7780
  • NAID: 120006348510
  • Peer Reviewed / Open Access
• [Journal Article] Insulin receptor substrate-1 associates with small nucleolar RNA which contributes to ribosome biogenesis. (2014)
  • Author(s): Ozoe A, Sone M, Fukushima T, Kataoka N, Chida K, Asano T, Hakuno F, Takahashi S-I.
  • Journal Title: Frontiers in Endocrinology Volume: 5 Pages: 24-24
  • DOI: 10.3389/fendo.2014.00024
  • Peer Reviewed / Open Access
• [Journal Article] Familial short stature is associated with a novel dominant-negative heterozygous insulin-like growth factor 1 receptor (IGF1R) mutation (2014)
  • Author(s): Kawashima Y, Hakuno F, Okada SI, Hotsubo T, Kinoshita T, Fujimoto M, Nishimura R, Fukushima T, Hanaki K, Takahashi SI, Kanzaki S
  • Journal Title: Clinical Endocrinology (Oxf) Volume: Epub ahead of print Issue: 2 Pages: 1-3
  • DOI: 10.1111/cen.12317
  • Peer Reviewed
• [Journal Article] Lactobacillus casei strain Shirota protects against non-alcoholic steatohepatitis development in a rodent model (2013)
  • Author(s): 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
  • Journal Title: American Journal Physiolgy-Gastrointestinal and Liver Physiogy Volume: 305 Issue: 12 Pages: 911-918
  • DOI: 10.1152/ajpgi.00225.2013
  • Peer Reviewed
• [Journal Article] Insulin Receptor Substrate-1 (IRS-1) Forms a Ribonucleoprotein Complex Associated with Polysomes (2013)
  • Author(s): Ozoe A, Sone M, Fukushima T, Kataoka N, Arai T, Chida K, Asano T, Hakuno F, Takahashi S-I
  • Journal Title: FEBS Lett. Volume: 587(15) Issue: 15 Pages: 2319-24
  • DOI: 10.1016/j.febslet.2013.05.066
  • Peer Reviewed
• [Journal Article] Par14 associates with IRS-1, thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions. (2013)
  • Author(s): 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.
  • Journal Title: Ｊournal of Biological Chemistry Volume: 288 Issue: 28 Pages: 20692-20701
  • DOI: 10.1074/jbc.m113.485730
  • Peer Reviewed
• [Journal Article] Resistin-Like Molecule β Is Abundantly Expressed in Foam Cells and Is Involved in Atherosclerosis Development. (2013)
  • Author(s): 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.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 33 Issue: 8 Pages: 1986-1993
  • DOI: 10.1161/atvbaha.113.301546
  • Peer Reviewed / Open Access
• [Journal Article] インスリン様活性と高齢化社会で克服すべき疾病 (2013)
  • Author(s): 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
  • Journal Title: 化学と生物 Volume: 51(6)
  • NAID: 10031177626
• [Journal Article] Valsartan Restores Inflammatory Response by Macrophages in Adipose and Hepatic Tissues of LPS-infused Mice. (2013)
  • Author(s): Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima T, Kumamoto S, Kamata H, Nishimura F, Asano T.
  • Journal Title: Adipocyte Volume: 未定
  • Peer Reviewed
• [Journal Article] Integrator complex plays anessential role inadipose differentiation (2013)
  • Author(s): 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.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 434 Issue: 2 Pages: 197-202
  • DOI: 10.1016/j.bbrc.2013.03.029
  • Peer Reviewed
• [Journal Article] Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. (2012)
  • Author(s): 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.
  • Journal Title: American Journal of Physiology - Endocrinology and Metabolism Volume: 302 Issue: 3 Pages: 286-296
  • DOI: 10.1152/ajpendo.00324.2011
  • Peer Reviewed
• [Journal Article] Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and atherosclerosis development (2012)
  • Author(s): 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.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Issue: 2 Pages: 291-298
  • DOI: 10.1161/atvbaha.111.234559
  • Peer Reviewed
• [Journal Article] Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation (2012)
  • Author(s): Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi JI, Hanaki K, Nanba E, Takahashi SI, Kanzaki S
  • Journal Title: Clin.Endocrinol. Volume: (in press) Issue: 2 Pages: 246-54
  • DOI: 10.1111/j.1365-2265.2012.04357.x
  • Peer Reviewed
• [Journal Article] Phosphatidylinositol 3-kinase-binding protein, PI3KAP/XB130, is required for cAMP-induced amplification of IGF mitogenic activity in FRTL-5 thyroid cells (2012)
  • Author(s): Yamanaka D, Akama T, Fukushima T, Nedachi T, Kawasaki C, Chida K, Minami S, Suzuki K, Hakuno F, Takahashi S-I.
  • Journal Title: Mol Endocrinol Volume: 26 Issue: 6 Pages: 1043
  • DOI: 10.1210/me.2011-1349
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 423 Issue: 1 Pages: 122-127
  • DOI: 10.1016/j.bbrc.2012.05.093
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Fukushima T, Nakamura Y, Yamanaka D, Shibano T, Chida K, Minami S, Asano T, Hakuno F, Takahashi S-I.
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 35 Pages: 29713-29721
  • DOI: 10.1074/jbc.m112.393074
  • Peer Reviewed
• [Journal Article] Role of Pin1 in the pathogenesis of non-alcoholic steatohepatitis in a rodent model (2012)
  • Author(s): 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
  • Journal Title: J Biol Chem Volume: 287 Issue: 53 Pages: 44526-44535
  • DOI: 10.1074/jbc.m112.397133
  • Peer Reviewed
• [Presentation] 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)
  • Author(s): Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Tomoichio Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • Organizer: Gordon Research Conference: IGF and Insulin System in Physiology and disease
  • Place of Presentation: Ventura, USA
  • Year and Date: 2015-03-08 – 2015-03-13
• [Presentation] Molecular mechanisms by which ubiquitin ligase Nedd4 enhances IRS-2-mediated IGF signaling (2014)
  • Author(s): Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Shin-Ichiro Takahashi, Tomoichiro Asano
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 神戸
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Xanthine oxidase inhibitor febuxostat improves nonalcoholic steatohepatitis (2014)
  • Author(s): Yasuka Matsunaga, Yusuke Nakatsu, Yasuyuki Seno, Aya Katasako, Ryuhei Kanaokam Toshiaki Fukushima, Hideaki Kamata, Tomoichiro Asano
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 神戸
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Roles of prolyl isomerase Pin1 in pancreatic beta cell function (2014)
  • Author(s): Yusuke Nakatsu, Keiichi Mori, Yasuka Matsunaga, Toshiaki Fukushima, Hideaki Kamata, Ken Yamaguchi, Hisamitsu Ishihara, Tomoichiro Asano
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 神戸
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 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)
  • Author(s): Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • Organizer: The International Congress of the GRS and the IGF Society
  • Place of Presentation: Singapore
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 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)
  • Author(s): 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
  • Organizer: The International Congress of the GRS and the IGF Society
  • Place of Presentation: Singapore
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] 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)
  • Author(s): Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Yasushi Saeki, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • Organizer: The 7h International Congress of the GRS and the IGF Society
  • Place of Presentation: Singapore
• [Presentation] 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)
  • Author(s): Yuka Narita, Atsufumi Ozoe, Toshiaki Fukushima, Naoyuki Kataoka, Akihiro Ito, Minoru Yoshida, Tomoichiro Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • Organizer: Japan Endocrine Society's Annual Meeting
  • Place of Presentation: 福岡
• [Presentation] Nedd4-IRS2 complex: mechanisms of the complex formation and its roles in prostate cancer cell proliferation (2013)
  • Author(s): 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
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 神戸
• [Presentation] 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)
  • Author(s): Haruka Furuta, Hidehito Yoshihara, Toshiaki Fukushima, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Tomoichio Asano, Kazuhiro Chida, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 神戸
• [Presentation] Ubiquitin-conjugation to IRS by ubiquitin ligase Nedd4 drives Insulin/IGF signaling. (2013)
  • Author(s): Toshiaki Fukushima
  • Organizer: Core-to-Core Project sponsored by JSPS (FY2012-FY2017) INTERNATIONAL OPEN WORKSHOP
  • Place of Presentation: Stockholm (スウェーデン)
  • Invited
• [Presentation] PGAM5, a mitochondrial protein phosphatase, regulates the serine/threonine phosphorylation status and stability of insulin receptor substrates. (2013)
  • Author(s): Yosuke Yoneyama, Junichi Inobe, Yukako Kida, Toshiaki Fukushima, Shiori Sekine, Tomoichiro Asano, Kazuhiro Chida, Kohsuke Takeda, Fumihiko Hakuno, Shin-Ichiro Takahashi
  • Organizer: Annual Meeting of the Molecular Biology Society of Japan,
  • Place of Presentation: 神戸
• [Presentation] Nedd4 potentiates IRS-2-mediated insulin/IGF signals and bioactivities. (2012)
  • Author(s): Fukushima T, Yoshihara H, Hakuno F, Saeki Y, Tanaka K, Ito A, Yoshida M, Nakatsu Y, Sakoda H, Kamata H, Takahashi SI, Asano T
  • Organizer: Annual Meeting of the Japan Diabetes Society
  • Place of Presentation: 横浜
• [Presentation] 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)
  • Author(s): Fukushima T, Yoshihara H, Hakuno F, Saeki Y, Tanaka K, Ito A, Yoshida M, Chida K, Sakoda H, Asano T, Takahashi SI.
  • Organizer: The 6th International Congress of the GRS and the IGF Society
  • Place of Presentation: ドイツ ミュンヘン
• [Remarks] 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/
• [Remarks] 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/