Insulin-like growth factor I synergizes with interleukin 4 for hematopoietic cell proliferation independent of insulin receptor substrate expression

作     者：Soon, L Flechner, L Gutkind, JS Wang, LH Baserga, R Pierce, JH Li, WQ 

作者机构：NCI Cellular & Mol Biol Lab Bethesda MD 20892 USA NIDR Oral & Pharyngeal Canc Branch Bethesda MD 20892 USA CUNY Mt Sinai Sch Med Dept Microbiol New York NY 10029 USA Thomas Jefferson Univ Kimmel Canc Ctr Philadelphia PA 19107 USA 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：1999年第19卷第5期

页      面：3816-3828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：衔接蛋白质类 信号转导 衔接蛋白质类 膜泡运输 钙-钙调素依赖性蛋白激酶类/代谢 细胞分裂 细胞系 酶激活 GRB2衔接蛋白质 基因表达调控/遗传学 基因 myc/遗传学 血细胞生成 胰岛素受体底物蛋白质类 胰岛素样生长因子Ⅰ/药理学 白细胞介素4/代谢 有丝分裂原/代谢 突变/遗传学 磷酸肌醇3-激酶类/代谢 磷蛋白类/遗传学 磷蛋白类/代谢 磷酰化 蛋白质类/代谢 受体蛋白质酪氨酸激酶类/代谢 受体 IGF1型/遗传学 受体 IGF1型/代谢 STAT6转录因子 Shc信号衔接蛋白质类 干细胞/代谢 反式激活因子类/代谢 转染 

摘      要：In the present study, we investigated the potential role of insulin-like growth factor I (IGF-I) receptor (IGF-IR) in cell proliferation by overexpressing it in 32D myeloid progenitor cells. The overexpression of IGF-IR caused the transfectants to proliferate in response to IGF-I in the absence of insulin receptor substrate (IRS) expression, The activation of overexpressed wild-type IGF-IR, but not that of an ATP-binding mutant of IGF-IR, resulted in the increased tyrosine phosphorylation of several intracellular proteins, including SHC, Src homology 2-containing inositol-5-phosphatase, protein kinase C-delta, and Erk2, Grb2 association with SHC and mitogen-activated protein kinase (MAPK) activity was also enhanced in response to IGF-I stimulation. Interestingly, the stimulation of the IGF-IR transfectants with interleukin 4 (IL-4) also resulted in strong mitogenesis independent of IRS expression. Moreover, IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants. IL-4 was able to synergize with IGF-I for DNA synthesis, even in the parental 32D cells and a pro-B-cell line, Baf3, indicating the physiological importance of the two growth factors in hematopoietic cell proliferation. IL-4 stimulation of the IGF-IR transfectants resulted in enhanced tyrosine phosphorylation of SHC, Erk2, and signal transducer and activator of transcription 6 (STAT6) proteins. Both IL-4 and IGF-I were able to induce c-myc early response gene expression, and this expression was maximal in the presence of both factors. Finally, we demonstrated that a MAPK kinase inhibitor was able to suppress mitogenesis of the IGF-IR transfectants in response to IGF-I and/or IL-4. Together, our results suggest that IL-4 synergizes with IGF-I for hematopoietic cell proliferation, likely through cross talk between SHC/Grb2/MAPK and STAT6 pathways and through c-myc gene up-regulation.