PMID- 28126338 OWN - NLM STAT- MEDLINE DCOM- 20170606 LR - 20180105 IS - 1090-2104 (Electronic) IS - 0006-291X (Linking) VI - 484 IP - 3 DP - 2017 Mar 11 TI - USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. PG - 522-528 LID - S0006-291X(17)30160-2 [pii] LID - 10.1016/j.bbrc.2017.01.101 [doi] AB - Insulin receptor substrates (IRSs) are phosphorylated by IGF-I receptor tyrosine kinase in a ligand-dependent manner. In turn, they bind to and activate effector proteins such as PI3K, leading to various cell responses including cell proliferation. We had reported that ubiquitin ligase Nedd4 induces mono-ubiquitination of IRS-2, thereby enhancing IRS-2 tyrosine phosphorylation, leading to increased IGF signaling and mitogenic activity. Here we show that ubiquitin-specific protease 15 (USP15) antagonizes the effect of Nedd4 on IRS-2. We identified USP15 as a protein that preferentially bound to IRS-2 when IRS-2 was conjugated with ubiquitin. In HEK293 cells, Nedd4 overexpression induced IRS-2 ubiquitination, which was decreased by USP15 co-expression while increased by USP15 knockdown. Nedd4 overexpression enhanced IGF-I-dependent IRS-2 tyrosine phosphorylation, and USP15 co-expression suppressed it. Conversely, USP15 knockdown increased IRS-2 tyrosine phosphorylation and downstream signaling in prostate cancer PC-3 cells. We concluded that USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Fukushima, Toshiaki AU - Fukushima T AD - Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan; Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan. FAU - Yoshihara, Hidehito AU - Yoshihara H AD - Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. FAU - Furuta, Haruka AU - Furuta H AD - Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan. FAU - Hakuno, Fumihiko AU - Hakuno F AD - Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan; Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan. FAU - Iemura, Shun-Ichiro AU - Iemura SI AD - 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. FAU - Natsume, Tohru AU - Natsume T AD - 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. FAU - Nakatsu, Yusuke AU - Nakatsu Y AD - Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan. FAU - Kamata, Hideaki AU - Kamata H AD - Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan. FAU - Asano, Tomoichiro AU - Asano T AD - Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan. FAU - Komada, Masayuki AU - Komada M AD - Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan. FAU - Takahashi, Shin-Ichiro AU - Takahashi SI AD - Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan; Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan. Electronic address: atkshin@mail.ecc.u-tokyo.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170123 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (Endosomal Sorting Complexes Required for Transport) RN - 0 (IRS2 protein, human) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Ubiquitinated Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases) RN - EC 2.3.2.26 (Nedd4 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 3.4.19.12 (USP15 protein, human) RN - EC 3.4.19.12 (Ubiquitin-Specific Proteases) SB - IM MH - Endosomal Sorting Complexes Required for Transport/*metabolism MH - HEK293 Cells MH - Humans MH - Insulin Receptor Substrate Proteins/*metabolism MH - Insulin-Like Growth Factor I/*metabolism MH - Nedd4 Ubiquitin Protein Ligases MH - Signal Transduction/*physiology MH - Ubiquitin-Protein Ligases/*metabolism MH - Ubiquitin-Specific Proteases/*metabolism MH - Ubiquitinated Proteins/metabolism MH - Ubiquitination/*physiology OTO - NOTNLM OT - Insulin receptor substrate (IRS)-2 OT - Insulin-like growth factor (IGF) OT - Nedd4 OT - Ubiquitin-specific protease 15 (USP15) OT - Ubiquitination EDAT- 2017/01/28 06:00 MHDA- 2017/06/07 06:00 CRDT- 2017/01/28 06:00 PHST- 2017/01/17 00:00 [received] PHST- 2017/01/19 00:00 [accepted] PHST- 2017/01/28 06:00 [pubmed] PHST- 2017/06/07 06:00 [medline] PHST- 2017/01/28 06:00 [entrez] AID - S0006-291X(17)30160-2 [pii] AID - 10.1016/j.bbrc.2017.01.101 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2017 Mar 11;484(3):522-528. doi: 10.1016/j.bbrc.2017.01.101. Epub 2017 Jan 23.