Mechanism of STAT3 activation by insulin-like growth factor I receptor

作     者：Zong, CS Chan, J Levy, DE Horvath, C Sadowski, HB Wang, LH 

作者机构：CUNY Mt Sinai Sch Med Dept Microbiol New York NY 10029 USA CUNY Mt Sinai Sch Med Dept Immunobiol New York NY 10029 USA CUNY Mt Sinai Sch Med Dept Biochem & Mol Biol New York NY 10029 USA NYU Dept Pathol New York NY 10016 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2000年第275卷第20期

页      面：15099-15105页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：细胞系 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢 胚胎 哺乳动物 胰岛素样生长因子Ⅰ/药理学 Janus激酶1 Janus激酶2 肌 骨骼 磷酰化 磷酸酪氨酸/代谢 蛋白酪氨酸激酶类/代谢 原癌基因蛋白质类 受体 IGF1型/遗传学 受体 IGF1型/生理学 重组蛋白质类/代谢 STAT3转录因子 反式激活因子类/遗传学 反式激活因子类/代谢 转染 动物 人类 小鼠 

摘      要：Recent evidence indicates that STAT proteins can be activated by a variety of receptor and non-receptor protein-tyrosine kinases, Unlike cytokine-induced activation of STATs, where JAKs are known to play a pivotal role in phosphorylating STATs, the mechanism for receptor protein-tyrosine kinase-mediated activation of STATs remains elusive. In this study, we investigated the activation of STAT proteins by the insulin-like growth factor I receptor (IGF-IR) in vitro and in vivo and assessed the role of JAKs in the process of activation. We found that STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. Moreover, tyrosine phosphorylation of STATS, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. Supporting the observation in 293T cells, endogenous STATS was tyrosine-phosphorylated upon IGF-I stimulation in the muscle cell line C2C12 as well as in various embryonic and adult mouse organs during different stages of development. Dominant-negative JAK1 or JAK2 was able to block the IGF-IR-mediated tyrosine phosphorylation of STATS in 293T cells. A newly identified family of proteins called SOCS (suppressor of cytokine signaling), including SOCS1, SOCS2, SOCS3 and CIS, was able to inhibit the IGF-I-induced STATS activation as well with varying degrees of potency, in which SOCS1 and SOCS3 appeared to have the higher inhibitory ability. Inhibition of STAT3 activation by SOCS could be overcome by overexpression of native JAK1 and JAK2. We conclude that IGF-I/IGF-IR is able to mediate activation of STATS in vitro and in vivo and that JAKs are essential for the process of activation.