Roles of Nedd4-IRS complexes in the development of diabetes and cancer

• Project/Area Number: 26460369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tokyo Institute of Technology (2015-2017); Hiroshima University (2014)
• Principal Investigator: Fukushima Toshiaki 東京工業大学, 科学技術創成研究院, 助教 (70543552)
• Co-Investigator(Renkei-kenkyūsha): SAEKI Yasushi 東京都医学総合研究所, 蛋白質代謝研究室, 副参事研究員 (80462779) ; ITO Akihiro 東京薬科大学, 生命科学部, 教授 (40391859)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• 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 / ユビキチン / がん / 糖尿病

Outline of Final Research Achievements

Insulin plays central roles in the regulation of glucose metabolism. Upon overnutrition, insulin target cells become resistant to insulin, and excessive resistance causes diabetes. Insulin-like growth factor (IGF) is a peptide similar in structure to insulin, and promotes body growth. Excessive sensitivity of cells to IGF contributes to hyper-proliferation and oncogenic transformation of cells. The mechanisms by which the responsiveness of cells to insulin/IGF is altered are not fully understood. In this study, we investigated intracellular signaling that is activated just after insulin/IGF binds to their membrane receptors. We found that IRS2, one of major insulin/IGF signal transducer proteins, associates with a protein called Nedd4. Our study indicated that the excessive disassembly of this Nedd4-IRS2 complex leads to insulin resistance and diabetes, whereas the excessive assembly contributes to hyper-proliferation of cancer cells.

Research Products

• [Int'l Joint Research] カロリンスカ研究所(スウェーデン)
• [Int'l Joint Research] 応用科学アッパーオーストリア大学(オーストリア)
• [Int'l Joint Research] ミシガン大学(米国)
• [Int'l Joint Research] カロリンスカ研究所(スウェーデン)
• [Int'l Joint Research] アッパーオーストラリア応用科学大学(オーストリア)
• [Int'l Joint Research] ミシガン大学(米国)
• [Int'l Joint Research] カロリンスカ研究所(スウェーデン)
• [Int'l Joint Research] 中国海洋大学(中国)
• [Journal Article] Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities (2018)
  • Author(s): Xie Xuan、Matsumoto Shunsuke、Endo Akinori、Fukushima Toshiaki、Kawahara Hiroyuki、Saeki Yasushi、Komada Masayuki
  • Journal Title: Journal of Cell Science Volume: 131 Issue: 8 Pages: 210856-210856
  • DOI: 10.1242/jcs.210856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glucose deprivation attenuates sortilin levels in skeletal muscle cells (2017)
  • Author(s): Ariga M, Yoneyama Y, Fukushima T, Ishiuchi Y, Ishii T, Sato H, Hakuno F, Nedachi T, Takahashi S
  • Journal Title: Endocrine Journal Volume: 64 Issue: 3 Pages: 255-268
  • DOI: 10.1507/endocrj.EJ16-0319
  • NAID: 130005529466
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Reduced SHARPIN and LUBAC formation may contribute to CCl4- or acetaminophen-induced liver cirrhosis in mice. (2017)
  • Author(s): Yamamotoya T, Nakatsu Y, Matsunaga Y, Fukushima T, Yamazaki H, Kaneko S, Fujishiro M, Kikuchi T, Kushiyama A, Tokunaga F, Asano T, and Sakoda H.
  • Journal Title: Int. J. Mol. Sci. Volume: 18 Issue: 2 Pages: 326-326
  • DOI: 10.3390/ijms18020326
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. (2017)
  • Author(s): Fukushima T, Yoshihara H, Furuta H, Hakuno F, Iemura SI, Natsume T, Nakatsu Y, Kamata H, Asano T, Komada M, Takahashi SI.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 484 Issue: 3 Pages: 522-528
  • DOI: 10.1016/j.bbrc.2017.01.101
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of X-linked protein kinase Nrk during pregnancy triggers breast tumor in mice (2016)
  • Author(s): Yanagawa T, Denda K, Inatani T, Fukushima T, Tanaka T, Kumaki N, Inagaki Y, Komada M
  • Journal Title: Am. J. Pathol. Volume: 186 Issue: 10 Pages: 2751-2760
  • DOI: 10.1016/j.ajpath.2016.06.005
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling (2016)
  • Author(s): L Girnita, S-I Takahashi, C Crudden, T Fukushima, C Worrall, H Furuta, H Yoshihara, F Hakuno, A Girnita
  • Journal Title: Progress in Molecular Biology and Translational Science Volume: 141 Pages: 277-311
  • DOI: 10.1016/bs.pmbts.2016.04.001
  • ISBN: 9780128093863
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. (2016)
  • Author(s): Okubo H, Kushiyama A, Sakoda H, Nakatsu Y, Iizuka M, Taki N, Fujishiro M, Fukushima T, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Asahara T, Yoshida Y, Chonan O, Encinas J, Asano T.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 20157-20157
  • DOI: 10.1038/srep20157
  • NAID: 120006796541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-molecular-mass complexes containing insulin receptor substrates play important roles in regulation of insulin-like activities. (2016)
  • Author(s): Takahashi SI, Fukushima T, Ando Y, Hakuno F.
  • Journal Title: Bioscience and Industry Volume: 74(1)
  • NAID: 40020705836
• [Journal Article] 甲状腺細胞の増殖誘導機構 (2016)
  • Author(s): Takahashi SI, Fukushima T, Yamanaka D, Hakuno F.
  • Journal Title: 甲状腺学会誌 Volume: 7(1)
• [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] The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. (2015)
  • Author(s): Nakatsu Y, Seno Y, Kushiyama A, Sakoda H, Fujishiro M, Katasako A, Mori K, Matsunaga Y, Fukushima T, Kanaoka R, Yamamotoya T, Kamata H, Asano T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 309(1) Issue: 1 Pages: G42-G51
  • DOI: 10.1152/ajpgi.00443.2014
  • Peer Reviewed
• [Journal Article] DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation. (2015)
  • Author(s): Shinjo T, Nakatsu Y, Iwashita M, Sano T, Sakoda H, Ishihara H, Kushiyama A, Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H, Nishimura F, Asano T.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 309(3) Issue: 3 Pages: E214-E223
  • DOI: 10.1152/ajpendo.00553.2014
  • Peer Reviewed
• [Journal Article] Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines. (2015)
  • Author(s): Kanaoka R, Kushiyama A, Seno Y, Nakatsu Y, Matsunaga Y, Fukushima T, Tsuchiya Y, Sakoda H, Fujishiro M, Yamamotoya T, Kamata H, Matsubara A, Asano T.
  • Journal Title: PLoS One. Volume: 10 (6) Issue: 6 Pages: e0127467-e0127467
  • DOI: 10.1371/journal.pone.0127467
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis. (2015)
  • Author(s): Matsunaga Y, Nakatsu Y, Fukushima T, Okubo H, Iwashita M, Sakoda H, Fujishiro M, Yamamotoya T, Kushiyama A, Takahashi S, Tsuchiya Y, Kamata H, Tokunaga F, Iwai K, Asano T.
  • Journal Title: Mediators Inflamm. Volume: 2015 Issue: 1 Pages: 125380-125380
  • DOI: 10.1155/2015/125380
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit (2015)
  • Author(s): Nakatsu Y, Iwashita M, Sakoda H, Ono H, Nagata K, Matsunaga Y, Fukushima T, Fujishiro M, Kushiyama A, Kamata H, Takahashi S, Katagiri H, Honda H, Kiyonari H, Uchida T, Asano T
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24255-24266
  • DOI: 10.1074/jbc.m115.658559
  • Peer Reviewed / Open Access
• [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] The Novel Functions of High-Molecular-Mass Complexes Containing Insulin Receptor Substrates in Mediation and Modulation of Insulin-Like Activities: Emerging Concept of Diverse Functions by IRS-Associated Proteins. (2015)
  • Author(s): Hakuno F, Fukushima T, Yoneyama Y, Kamei H, Ozoe A, Yoshihara H, Yamanaka D, Shibano T, Sone-Yonezawa M, Yu BC, Chida K, Takahashi S.
  • Journal Title: Front Endocrinol (Lausanne). Volume: 6 Pages: 73-73
  • DOI: 10.3389/fendo.2015.00073
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Nedd4-induced mono-ubiquitination of IRS-2 enhances IGF/insulin signaling through a novel mechanism (2017)
  • Author(s): 福嶋俊明
  • Organizer: Core-to-Core Program “New Insights into the Molecular Basis of Prevention of Diseases in the Aging Society Caused by Modulation of Insulin-Like Activities” International Seminar
  • Place of Presentation: 東京
  • Year and Date: 2017-01-24
  • Int'l Joint Research / Invited
• [Presentation] クッシング病で見られる脱ユビキチン化酵素USP8の変異は バソプレシン受容体V1bの安定化を引き起こす (2016)
  • Author(s): 福嶋俊明 川口紘平 遠藤 彬則 駒田雅之
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] クッシング病における変異型USP8によるバソプレシン受容体V1bの安定化 (2016)
  • Author(s): 福嶋俊明
  • Organizer: 新学術領域【ユビキチンネオバイオロジー】第3回領域会議
  • Place of Presentation: 札幌
  • Year and Date: 2016-11-16
• [Presentation] インスリン受容体基質IRSはG3BP1と相互作用し、 cap非依存的翻訳を促進する (2016)
  • Author(s): 中沖優里、尾添淳文、曽根芽里、山中大介、福嶋俊明、片岡直行、浅野知一郎、 千田和広、伯野史彦、高橋伸一郎
  • Organizer: 日本農芸化学会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-27
• [Presentation] クッシング病で見られる脱ユビキチン化酵素USP8の変異体は ACTH分泌を制御するバソプレシン受容体V1bを安定化する (2015)
  • Author(s): 福嶋俊明
  • Organizer: 新学術領域【ユビキチンネオバイオロジー】第２回領域会議
  • Place of Presentation: 南房総
  • Year and Date: 2015-12-16
• [Presentation] 非アルコール性脂肪性肝炎におけるLUBAC形成障害の解析 (2015)
  • Author(s): 松永 泰花、中津 祐介、福嶋 俊明、大久保 博史、岩下 未咲、迫田 秀之、藤城 緑、山本屋 武、櫛山 暁史、高橋 伸一郎、土谷 佳弘、鎌田 英明、徳永 文稔、岩井 一宏、浅野 知一郎
  • Organizer: 日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 脳下垂体の腫瘍性疾患クッシング病における脱ユビキチン化酵素USP8の活性化変異 (2015)
  • Author(s): 駒田 雅之、川口 紘平、Arif Ibrahim Ardisasmita、福嶋 俊明
  • Organizer: 日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Nedd4-induced monoubiquitination of IRS-2 enhances IGF signaling and mitogenic activity (2015)
  • Author(s): 福嶋俊明
  • Organizer: 新学術領域【ユビキチンネオバイオロジー】若手ワークショップ
  • Place of Presentation: 京都
  • Year and Date: 2015-07-01
• [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 Beach Marriott, 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: 神戸ポートアイランド, 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: 神戸ポートアイランド, 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: 神戸ポートアイランド, 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: Suntec Convention & Exhibition Centre, Suntec City, 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: Suntec Convention & Exhibition Centre, Suntec City, Singapore
  • Year and Date: 2014-10-15 – 2014-10-18
• [Book] Progress in Molecular Biology and Translational Science: When Phosphorylation Encounters Ubiquitination: A Balanced Perspective on IGF-1R Signaling (2016)
  • Author(s): L. Girnita, SI. Takahashi, C. Crudden, T. Fukushima, C. Worrall, H. Furuta, H. Yoshihara, F. Hakuno, A. Girnita
  • Publisher: Elsevier Inc.
• [Remarks] 動物の成長や細胞の増殖の新しい調節機構を発見 (東京大学、UTokyo Research)*
  • URL: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.html
• [Remarks] 東京大学 大学院農学生命科学研究科 動物細胞制御学研究室
  • URL: http://endo.ar.a.u-tokyo.ac.jp/shingroup/index.html
• [Remarks] 広島大学 医歯薬保健学研究院 医化学研究室
  • URL: http://home.hiroshima-u.ac.jp/ikagaku/
• [Remarks] 東京工業大学 科学技術創成研究院 細胞制御工学研究センター 駒田研究室
  • URL: https://komada-lab.jimdo.com/
• [Remarks] 動物の成長や細胞の増殖の新しい調節機構を発見（東京大学、UTokyo Research）*
  • URL: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.html
• [Remarks] 東京工業大学 科学技術創成研究院 細胞制御工学研究ユニット 駒田研究室
  • URL: http://komada-lab.jimdo.com/