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首页> 外文期刊>Molecular and Cellular Biology >Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors
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Differential Activation of Insulin Receptor Substrates 1 and 2 by Insulin-Like Growth Factor-Activated Insulin Receptors

机译：胰岛素样生长因子激活的胰岛素受体的胰岛素受体底物1和2的差异激活。

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The insulin-like growth factors (insulin-like growth factor I [IGF-I] and IGF-II) exert important effects on growth, development, and differentiation through the IGF-I receptor (IGF-IR) transmembrane tyrosine kinase. The insulin receptor (IR) is structurally related to the IGF-IR, and at high concentrations, the IGFs can also activate the IR, in spite of their generally low affinity for the latter. Two mechanisms that facilitate cross talk between the IGF ligands and the IR at physiological concentrations have been described. The first of these is the existence of an alternatively spliced IR variant that exhibits high affinity for IGF-II as well as for insulin. A second phenomenon is the ability of hybrid receptors comprised of IGF-IR and IR hemireceptors to bind IGFs, but not insulin. To date, however, direct activation of an IR holoreceptor by IGF-I at physiological levels has not been demonstrated. We have now found that IGF-I can function through both splice variants of the IR, in spite of low affinity, to specifically activate IRS-2 to levels similar to those seen with equivalent concentrations of insulin or IGF-II. The specific activation of IRS-2 by IGF-I through the IR does not result in activation of the extracellular signal-regulated kinase pathway but does induce delayed low-level activation of the phosphatidylinositol 3-kinase pathway and biological effects such as enhanced cell viability and protection from apoptosis. These findings suggest that IGF-I can function directly through the IR and that the observed effects of IGF-I on insulin sensitivity may be the result of direct facilitation of insulin action by IGF-I costimulation of the IR in insulin target tissues.
机译：胰岛素样生长因子（胰岛素样生长因子I [IGF-I]和IGF-II）通过IGF-I受体（IGF-IR）跨膜酪氨酸激酶对生长，发育和分化产生重要影响。胰岛素受体（IR）在结构上与IGF-IR相关，并且在高浓度下，尽管IGF对IR的亲和力通常较低，但它们也可以激活IR。已经描述了在生理浓度下促进IGF配体和IR之间的串扰的两种机制。这些中的第一个是存在选择性剪接的IR变体，其对IGF-II和胰岛素表现出高亲和力。第二种现象是由IGF-1R和IR半抗原受体组成的杂合受体结合IGF而不是胰岛素的能力。然而，迄今为止，尚未证明IGF-I在生理水平上直接激活IR全息感受器。现在我们发现，尽管亲和力很低，IGF-I仍可以通过IR的两个剪接变体起作用，以将IRS-2特异性激活至与等效浓度的胰岛素或IGF-II相似的水平。 IGF-1通过IR对IRS-2的特异性激活不会导致细胞外信号调节激酶途径的激活，但会引起磷脂酰肌醇3激酶途径的延迟低水平激活以及生物学效应，例如增强的细胞活力和防止凋亡。这些发现表明，IGF-I可以直接通过IR起作用，并且所观察到的IGF-I对胰岛素敏感性的作用可能是胰岛素靶组织中IR的IGF-I共刺激直接促进胰岛素作用的结果。

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