title: Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity.
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.
authors: 1] Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2] Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
authors: Toshiaki
authors: T
authors: Fukushima
authors: 1] Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Hidehito
authors: H
authors: Yoshihara
authors: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors: Haruka
authors: H
authors: Furuta
authors: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors: Hiroyasu
authors: H
authors: Kamei
authors: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors: Fumihiko
authors: F
authors: Hakuno
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, Shandong 266003, China.
authors: Jing
authors: J
authors: Luan
authors: Department of Molecular, Cellular and Developmental Biology, University of Michigan, 830 North University, Ann Arbor, Michigan 48109, USA.
authors: Cunming
authors: C
authors: Duan
authors: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Yasushi
authors: Y
authors: Saeki
authors: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Keiji
authors: K
authors: Tanaka
authors: Translational Research Center, Fukushima Medical University, 11-25 Sakaemachi, Fukushima City, Fukushima 960-8031, Japan.
authors: Shun-Ichiro
authors: S
authors: Iemura
authors: Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
authors: Tohru
authors: T
authors: Natsume
authors: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors: Kazuhiro
authors: K
authors: Chida
authors: Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
authors: Yusuke
authors: Y
authors: Nakatsu
authors: Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
authors: Hideaki
authors: H
authors: Kamata
authors: Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
authors: Tomoichiro
authors: T
authors: Asano
authors: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors: Shin-Ichiro
authors: S
authors: Takahashi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008938:Mitosis / Q000235:genetics*; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013002:Somatomedins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D054875:Ubiquitination; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D056827:Endosomal Sorting Complexes Required for Transport; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D013002:Somatomedins; D029961:Zebrafish Proteins; C114154:epsin; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1