Full text

Turn on search term navigation

Copyright Nature Publishing Group Apr 2015

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.

Details

Title
Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity
Author
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
Pages
6780
Publication year
2015
Publication date
Apr 2015
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1673371151
Copyright
Copyright Nature Publishing Group Apr 2015