2013 Fiscal Year Final Research Report
Novel mechanisms of growth regulation through changes in ubiquitination of insulin receptor substrates
| Project/Area Number |
22248030
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied animal science
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
HAKUNO Fumihiko 東京大学, 大学院農学生命科学研究科, 助教 (30282700)
NISHIHARA Masugi 東京大学, 大学院農学生命科学研究科, 教授 (90145673)
ITO Akihiro 独立行政法人理化学研究所, 吉田化学遺伝学研究室, 専任研究員 (40391859)
YASUSHI Saeki 公益財団法人東京都医学総合研究所, 吉田化学遺伝学研究室, 主席研究員 (80462779)
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| Project Period (FY) |
2010-05-31 – 2013-03-31
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| Keywords | 代謝・内分泌制御 / インスリン様成長因子 / インスリン受容体基質 / ユビキチン化酵素 / 脱ユビキチン化酵素 / 細胞内シグナル / インスリン様活性 |
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| Research Abstract |
Insulin receptor substrates (IRSs) that are phosphorylated by insulin-like growth factor (IGF)-I receptor tyrosine kinases. Phosphotyrosyl IRSs are recognized by signaling molecules possessing SH2 domains, which mediate various IGF bioactivities. However, we have shown that IRSs are also associated with other proteins by a phosphotyrosine-independent mechanism. These protein complexes contain a number of ubiquitin ligases (E3) and deubiquitinating enzymes (DUBs). Our results indicate that ubiquitination of IRSs which was dynamically regulated by these E3 and DUBs in response to other extracellular factor, plays important roles not only in regulation of their protein levels but also modulation of their tyrosine phosphorylation, leading to control of IGF bioactivities, such as a growth-promoting activity.
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[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 IRSs2012
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
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Journal Title
Biochem. Biophys. Res. Commun.
Volume: 423
Pages: 122-127
DOI
Peer Reviewed
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[Journal Article] HSP90 interacting with IRS-2 is involved in cAMP-dependent potentiation of IGF-I signals in FRTL-5 cells2011
Author(s)
Fukushima T, Okajima H, Yamanaka D, Ariga-Nedachi M, Nagata S, Ito A, Yoshida M, Asano T, Minami S, Chida K, Hakuno F, Takahashi S-I
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Journal Title
Mol Cell Endocrinol.
Volume: 344
Pages: 81-89
DOI
Peer Reviewed
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[Journal Article] Insulin receptor substrates form high-molecular-mass complexes that modulate their availability to insulin/insulin-like growth factor-I receptor tyrosine kinases2011
Author(s)
Fukushima T, Arai T, Ariga M, Okajima H, Ooi Y, Iijima Y, Sone M, Cho Y, Ando Y, Kasahara K, Ozoe A, Yoshihara H, Chida K, Okada S, Kopchick JJ, Hakuno F, Takahashi S-I
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Journal Title
Biochem Biophys Res Commun.
Volume: 404
Pages: 767-773
DOI
Peer Reviewed
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[Presentation] A deubiquitinating enzyme, USP7, is associated with insulin receptor substrate (IRS)-2 forming a negative feedback loop in insulin/IGF signaling2013
Author(s)
Hidehito Yoshihara, Toshikai Fukushima, Furuta Haruka, Fumihiko Hakuno, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Shunichiro Iemura, Tohru Natsume, Shin-Ichiro Takahashi
Organizer
EMBO Conference"Ubiquitin and ubiquitin-like proteins : from structure to function
Place of Presentation
Riva del Garda, Italy
Year and Date
20131001-05
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[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 mechanism2012
Author(s)
Toshiaki Fukushima, Hidehito Yoshihara, Fumihiko Hakuno, Yasushi Saeki, Keiji Tanaka, Akihiro Ito, Minoru Yoshida, Kazuhiro Chida, Hideyuki Sakoda, Tomoichiro Asano, and Shin-Ichiro Takahashi
Organizer
The 6th Interntional Congress of the GRS-IGF Society
Place of Presentation
Munich, Germany
Year and Date
2012-10-20
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