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

Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Hiroyasu Kamei, Fumihiko Hakuno, Jing Luan, Cunming Duan, Yasushi Saeki, Keiji Tanaka, Shun-Ichiro Iemura, Tohru Natsume, Kazuhiro Chida, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano and Shin-Ichiro Takahashi ()
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Toshiaki Fukushima: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Hidehito Yoshihara: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Haruka Furuta: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Hiroyasu Kamei: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Fumihiko Hakuno: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Jing Luan: Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China
Cunming Duan: Cellular and Developmental Biology, University of Michigan
Yasushi Saeki: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Keiji Tanaka: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Shun-Ichiro Iemura: Translational Research Center, Fukushima Medical University
Tohru Natsume: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST)
Kazuhiro Chida: Graduate School of Agriculture and Life Sciences, The University of Tokyo
Yusuke Nakatsu: Graduate School of Medicine, Hiroshima University
Hideaki Kamata: Graduate School of Medicine, Hiroshima University
Tomoichiro Asano: Graduate School of Medicine, Hiroshima University
Shin-Ichiro Takahashi: Graduate School of Agriculture and Life Sciences, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7780

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