Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-α or EGF, augments pancreatic β-cell proliferation
Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-α or EGF, augments pancreatic β-cell proliferation
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DOI：
10.2337/diabetes.51.4.966
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发表时间：
2002-04-01
期刊：
影响因子：
7.7
通讯作者：
Rhodes, CJ
中科院分区：
文献类型：
--
作者：
Lingohr, MK;Dickson, LM;Rhodes, CJ
将转化生长因子(TGF)- α -和表皮生长因子(EGF)-诱导的信号转导与胰岛素样生长因子-1 （IGF-1）在INS-1细胞中的信号转导进行直接比较。tgf - α /EGF瞬时（20倍），糖原合成酶激酶(GSK)-3（> 10倍）和蛋白激酶B (PKB) (Ser（473）和Thr(308))，但不增加[H-3]胸腺嘧啶的掺入。相比之下，Erk1/2、GSK-3和PKB在葡萄糖和IGF-1作用下的磷酸化时间更长（约24小时），虽然不如tgf - α /EGF那样强劲，但确实增加了p细胞的增殖。IGF-1/葡萄糖也增加了p70（S6K）的磷酸化，但tgf - α /EGF没有增加，尽管上游PKB被激活。研究发现，IGF-1诱导磷脂酰肌醇3-激酶（PI3K）以葡萄糖依赖的方式与胰岛素受体底物(IRS)-1和-2结合，而tgf - α /EGF则没有。与对照或腺病毒介导的IRS-1过表达的INS-1细胞相比，腺病毒介导的IRS-2过表达进一步增加了葡萄糖/ igf -1诱导的β细胞增殖（超过两倍，P < 0.05），强调了IRS-2介导的特异性信号事件的重要性。IRS-1和IRS-2过表达均未诱导β细胞对tgf - α /EGF的增殖反应。因此，Erk1/2和PI3K信号通路的长时间激活在使β细胞发生有丝分裂事件中是重要的，并且这种持续激活很可能是由IRS-2特异性发生的信号转导引起的。
Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. TGF-alpha/EGF transiently (20-fold), glycogen synthase kinase (GSK)-3 (> 10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [H-3]thymidine incorporation. In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase P-cell proliferation. Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2.