Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development
Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development
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DOI：
10.1016/s0016-5085(03)00893-x
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发表时间：
2003-08-01
期刊：
影响因子：
29.4
通讯作者：
Wands, JR
中科院分区：
文献类型：
--
作者：
Khamzina, L;Gruppuso, PA;Wands, JR
背景与目的：胰岛素生长因子信号转导通路是成体肝细胞增殖的重要调节因子。本研究的目的是确定胰岛素受体底物（IRS-1 和 IRS-2）介导的生长级联在快速生长的胎鼠肝脏中的作用。方法：我们测定了发育过程中和成年肝脏中存在或不存在胰岛素刺激的情况下胰岛素受体β亚基（IRbeta）、IRS-1和IRS-2的表达和酪氨酰磷酸化、磷脂酰肌醇3激酶（PIU）的结合以及丝裂原激活蛋白激酶（MAPK）通路的激活。此外，还研究了其他下游成分的激活，包括 PI3K、Akt、GSK3beta、Bad 和 p70S6 激酶。结果：我们观察到与成人肝脏相比，胎儿肝脏中 IRS-1 的表达和酪氨酰磷酸化降低。这些发育变化导致对胰岛素刺激和随后的 PI3K 和 MAPK 级联下游激活缺乏敏感性，直到新生儿后期。相比之下，早在胚胎第15天就有高水平的IRS-2表达和胰岛素刺激的酪氨酰磷酸化，并具有强大的PI3K结合和激活，这可能会增强肝脏快速生长期的肝细胞存活率。结论：IRS-1 信号转导通路在胎儿肝脏生长中并不起主要作用，因为 IRS-2 在早期发育中充当主要的胰岛素反应分子。然而，胰岛素介导的 IRS-1/MAPK 级联激活有助于成人的生长。
Background & Aims: The insulin growth factor signal transduction pathway is an important regulator of adult hepatocyte proliferation. The purpose of this study was to determine the roles of the insulin receptor substrate (IRS-1 and IRS-2)-mediated growth cascades in rapidly growing fetal rat liver. Methods: We determined the expression and tyrosyl phosphorylation of the insulin receptor beta subunit (IRbeta), IRS-1 and IRS-2, the binding of phosphatidylinositol 3-kinase (PIU), and activation of the mitogen-activated protein kinase (MAPK) pathway in the presence or absence of insulin stimulation in vivo during development and in the adult liver. In addition, activation of other downstream components including PI3K, Akt, GSK3beta, Bad, and p70S6 kinase was studied. Results: We observed reduced expression and tyrosyl phosphorylation of IRS-1 in the fetal liver compared with the adult liver. These developmental changes resulted in a lack of sensitivity to insulin stimulation and subsequent downstream activation of the PI3K and MAPK cascades until the postneonatal period. In contrast, there was a high level of IRS-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust PI3K binding and activation, which may enhance hepatocyte survival during the rapid growth phase of the liver. Conclusions: The IRS-1 signal transduction pathway does not play a major role in fetal liver growth because IRS-2 functions as the major insulin responsive molecule in early development. However, insulin-mediated IRS-1/MAPK cascade activation contributes to growth in the adult.