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

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  • Toshiaki Fukushima

    (Graduate School of Agriculture and Life Sciences, The University of Tokyo
    Graduate School of Medicine, Hiroshima University)

  • Hidehito Yoshihara

    (Graduate School of Agriculture and Life Sciences, The University of Tokyo
    Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science)

  • 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)

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.

Suggested Citation

  • Toshiaki Fukushima & Hidehito Yoshihara & Haruka Furuta & Hiroyasu Kamei & Fumihiko Hakuno & Jing Luan & Cunming Duan & Yasushi Saeki & Keiji Tanaka & Shun-Ichiro Iemura & Tohru Natsume & Kazuhiro Chi, 2015. "Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7780
    DOI: 10.1038/ncomms7780
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    Cited by:

    1. Iman Lohraseb & Peter McCarthy & Genevieve Secker & Ceilidh Marchant & Jianmin Wu & Naveid Ali & Sharad Kumar & Roger J. Daly & Natasha L. Harvey & Hiroshi Kawabe & Oded Kleifeld & Sophie Wiszniak & Q, 2022. "Global ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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