Others Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Fukushima, Toshiaki  ,  Yoshihara, Hidehito  ,  Furuta, Haruka  ,  Kamei, Hiroyasu  ,  Hakuno, Fumihiko  ,  Luan, Jing  ,  Duan, Cunming  ,  Saeki, Yasushi  ,  Tanaka, Keiji  ,  Iemura, Shun-Ichiro  ,  Natsume, Tohru  ,  Chida, Kazuhiro  ,  Nakatsu, Yusuke  ,  Kamata, Hideaki  ,  Asano, Tomoichiro  ,  Takahashi, Shin-Ichiro

62015-04-15 , Nature Publishing Group , Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo , Department of Medical Science, Graduate School of Medicine, Hiroshima University , Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science , Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China , Department of Molecular, Cellular and Developmental Biology, University of Michigan , Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST)
ISSN:2041-1723 (online)
UTokyo Research掲載「動物の成長や細胞の増殖の新しい調節機構を発見」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.html
UTokyo Research "Novel regulatory mechanisms of animal growth and cell proliferation" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.html
Insulin-like growth factors (IGFs) induce proliferation of various cell types and play important roles in somatic growth and cancer development. Phosphorylation of insulin receptor substrate (IRS)-1/2 by IGF-I receptor tyrosine kinase is essential for IGF action. Here we identify Nedd4 as an IRS-2 ubiquitin ligase. Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin-binding protein. Nedd4 recruits IRS-2 to the membrane, probably through promoting Epsin1 binding, and enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation. In thyroid FRTL-5 cells, activation of the cyclic AMP pathway increases the association of Nedd4 with IRS-2, thereby enhancing IRS-2-mediated signalling and cell proliferation induced by IGF-I. The Nedd4 and IRS-2 association is also required for maximal activation of IGF-I signalling and cell proliferation in prostate cancer PC-3 cells. Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo. We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity.



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