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.
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.
Nat Commun. 2015 Apr 16;6:6780. doi: 10.1038/ncomms7780.
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.
胰岛素样生长因子（IGFs）诱导各种细胞类型的增殖，并在躯体生长和癌症发展中发挥重要作用。胰岛素受体底物（IRS）-1/2 的磷酸化由 IGF-1 受体酪氨酸激酶介导，是 IGF 作用所必需的。在这里，我们确定 Nedd4 是 IRS-2 的泛素连接酶。Nedd4 单泛素化 IRS-2，促进其与 Epsin1（一种泛素结合蛋白）结合。Nedd4 将 IRS-2 募集到膜上，可能是通过促进 Epsin1 结合，从而增强 IGF-1 受体诱导的 IRS-2 酪氨酸磷酸化。在甲状腺 FRTL-5 细胞中，cAMP 通路的激活增加了 Nedd4 与 IRS-2 的结合，从而增强了 IRS-2 介导的信号转导和 IGF-I 诱导的细胞增殖。Nedd4 和 IRS-2 的结合对于前列腺癌 PC-3 细胞中 IGF-I 信号转导和细胞增殖的最大激活也是必需的。Nedd4 过表达通过体内 IRS-2 加速斑马鱼胚胎生长。我们的结论是，Nedd4 诱导的 IRS-2 单泛素化增强了 IGF 信号转导和有丝分裂活性。
