STRUCTURAL AND FUNCTIONAL HOMOLOGIES IN THE RECEPTORS FOR INSULIN AND THE INSULIN-LIKE GROWTH-FACTORS
STRUCTURAL AND FUNCTIONAL HOMOLOGIES IN THE RECEPTORS FOR INSULIN AND THE INSULIN-LIKE GROWTH-FACTORS
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DOI：
10.1016/0092-8674(82)90399-3
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发表时间：
1982-01-01
期刊：
影响因子：
64.5
通讯作者：
CZECH, MP
中科院分区：
文献类型：
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作者：
CZECH, MP
胰岛素与胰岛素样生长因子I和II(IGF-I和IGF-II)两个相关多肽的细胞反应的协调是多肽激素作用领域中的一个有趣的问题。这三个配体的肽结构非常相似，因为它们有相当大的氨基酸序列同源性，并且它们的结构中有相似的二硫键位置(Rinderkeck ht和Humbel，JBC 253,2769-2776,1978；Rinderkeck ht和Humbel，FEBS Lett)。89年，283-286,1978年)。胰岛素和IGFS之间的一个有趣的区别是后者保留了在胰岛素原转化为胰岛素时丢失的连接肽结构元件。因此，胰岛素样生长因子多肽是单链的，而胰岛素含有两个二硫键连接的多肽。IGF-I和IGF-II是由肝脏分泌的，尽管其他未知的组织也可能对它们的产生起到重要作用。肝脏产生的IGF-I相当严格地受垂体生长激素的调节，并可能在调节这种激素的生长效应中起关键作用。相比之下，IGF-II的产生不依赖于生长激素，其确切的生理作用尚不清楚。胰岛素的分泌/？胰腺细胞对葡萄糖和氨基酸等循环底物高度敏感。因此，这一家族多肽的循环水平的来源和调节似乎是完全不同的。应该注意的是，术语生长原子素、增殖刺激活性和不可抑制的胰岛素样活性也被用来定义与胰岛素样生长因子相似或相同的多肽(Giordano等，ed.体细胞生长和生长。Serono研讨会论文集，23，学术出版社，第#页。L-95,1979；雷克勒等人，J.苏普拉莫尔。结构。75,253-256,1981年)。胰岛素、IGF-I和IGF-II对靶组织的生物学作用可分为两类：一类涉及膜转运系统或酶活性的快速调节，另一类起效时间较长，似乎涉及转录或DNA复制的调节。在过去的十年里，用提纯的多肽进行的实验产生了描述性的结果，说明了胰岛素和IGF作用的两个基本且相当矛盾的元素。首先，对‘251标记的多肽与细胞和膜的结合的研究表明，存在着不同的受体物种，它们对不同的配体表现出交叉反应。例如，人胎盘中的胰岛素受体与高亲和力的胰岛素结合，与亲和力较低的IGF-II结合，与亲和力最低的IGF-I结合。然而，对这些研究结果的仔细分析显示，在所研究的组织中，这三种配体与假定受体的相对结合亲和力存在很大差异。这表明，大量不同的受体结构可能解释了观察到的结合特性的巨大差异(Rechler等人，Endocrinology 707,1451-1459,1980)。第二，通常观察到低生理浓度的胰岛素而不是IGF-I或IGF-II来调节快速的细胞反应，如靶组织中增加的运输活动。需要高浓度的IGFS才能引起这些反应。相反，观察到低浓度的IGF-I和IGF-II能够刺激DNA复制和细胞增殖，而高浓度的胰岛素能够模拟这些效应。这些数据与生长因子受体介导细胞增殖和胰岛素受体介导细胞快速反应的假设是一致的。然而，…出现了关键的例外情况
One of the fascinating problems in the field of peptide hormone action is the coordination of cellular responses to insulin and the two related peptides, insulin-like growth factor I and II (IGF-I and IGF-II). The peptide structures of the three ligands are quite similar in that they share considerable amino acid sequence homology and the similar positioning of disulfide bonds within their structures (Rinderknecht and Humbel, JBC 253, 2769-2776, 1978; Rinderknecht and Humbel, FEBS Lett. 89, 283-286, 1978). An interesting distinction between insulin and IGFs is the retention by the latter of the connecting peptide structural element that is lost upon conversion of proinsulin to insulin. Thus the insulin-like growth factor polypeptides are single chains, while insulin contains two disulfide-linked polypeptides. IGF-I and IGF-II are secreted by the liver, although other, as yet unknown tissues may also contribute significantly to their production. IGF-I production by the liver is regulated quite strictly by pituitary growth hormone and may play a key role in mediating the growth effects of this hormone. In contrast, IGF-II production does not depend on growth hormone, and its precise physiological role is not understood. Insulin secretion by the/? cells of the pancreas is highly sensitive to circulating substrates such as glucose and amino acids. Thus the source and regulation of circulating levels of this family of peptides appear to be quite different. It should be noted that the terms somatomedins, multiplicationstimulating activity and nonsuppressible insulin-like activity have also been used to define polypeptides similar or identical to the insulin-like growth factors (Giordano et al., eds. Somatomedins and Growth. Proceedings of the Serono Symposia, 23, Academic Press, pp. l-95, 1979; Rechler et al., J. Supramol. Struct. 75, 253-256, 1981). The biological actions of insulin, IGF-I and IGF-II on target tissues can be divided into two types: those that involve the rapid modulation of membrane-transport systems or enzyme activities, and those that are longer in onset and appear to involve regulation of transcription or DNA replication. Experiments performed over the last decade with the purified peptides produced descriptive results that illustrate two basic and rather paradoxical elements of insulin and IGF action. First, studies on the binding of the ‘251-labeled peptides to cells and membranes indicated that distinct receptor species were present that exhibited cross-reactivity for the various ligands. For example, the insulin receptor in human placenta that bound insulin with high affinity bound IGF-II with lower affinity, and IGF-I with lowest affinity. Yet careful analysis of the results of these studies showed a large number of differences among the tissues studied in the relative binding affinities of the three ligands to the putative receptors. This suggested the possibility that a large number of heterogeneous receptor structures might account for the great diversity of binding characteristics observed (Rechler et al., Endocrinology 707, 1451-1459, 1980).Second, low physiological concentrations of insulin but not of IGF-I or IGF-II were normally observed to modulate the rapid cellular responses, such as increased transport activities in target tissues. High concentrations of the IGFs were required to elicit these responses. In contrast, low concentrations of IGF-I and IGF-II were observed to stimulate DNA replication and cell proliferation, while high concentrations of insulin were able to mimic these effects. These data were consistent with the hypothesis that the growth factor receptors mediated cell proliferation and insulin receptors mediated the rapid cellular responses. Yet critical exceptions arose …