The insulin signaling system.
The insulin signaling system.
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DOI：
10.1016/s0021-9258(17)42297-6
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发表时间：
1994-01
期刊：
影响因子：
--
通讯作者：
M. White;C. Kahn
中科院分区：
文献类型：
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作者：
M. White;C. Kahn
在哺乳动物中，胰岛素是控制血糖的主要激素，通过刺激肌肉和脂肪细胞中的葡萄糖流入和代谢以及抑制肝脏的胰岛素生成来起作用。此外，胰岛素改变几乎所有胰腺中多种酶和转运系统的表达或活性。胰岛素作用是通过胰岛素受体介导的，胰岛素受体是一种具有内在蛋白酪氨酸激酶活性的跨膜糖蛋白。酪氨酸激酶的活性水平反映了血清中胰岛素的浓度，并且似乎通过受体本身和底物如胰岛素受体底物-1（IRS-1）的酪氨酸磷酸化来介导胰岛素反应。非胰岛素依赖型糖尿病在很大程度上是由于胰岛素抵抗，即靶细胞不再对正常水平的循环胰岛素产生反应的状态。为了了解正常代谢的控制机制以及非胰岛素依赖型糖尿病的发病机制，了解胰岛素受体所使用的信号通路是至关重要的。许多质膜受体通过蛋白酪氨酸激酶调节细胞过程。胰岛素受体与表皮生长因子（EGF）和血小板衍生生长因子（PDGF）受体一样，含有内在酪氨酸激酶活性（1）。T和B细胞上的抗原受体以及生长激素、促红细胞生成素和几种细胞因子的受体不具有内在酪氨酸激酶活性，但通过与细胞质酪氨酸激酶如Fyn、Tyk-2或Jak-1和-2结合刺激酪氨酸磷酸化（2，3）。在每种情况下，配体结合激活相关的酪氨酸激酶，并且对于受体酪氨酸激酶，大多数证据表明这一步骤对于生物活性是必不可少的。激活的受体经常在胞质结构域中的酪氨酸残基上进行自磷酸化。为了传播信号，许多自磷酸化受体直接结合到含有Src同源2结构域的蛋白质（SH 2蛋白）。SH 2蛋白的结合取决于每个受体中酪氨酸自磷酸化位点周围的氨基酸序列（4）。EGF和PDGF受体在不同程度上与磷脂酰肌醇（PI）3 ′-激酶、p21 m ″-GAP、磷脂酶Cy、GRB-2（一种连接酪氨酸激酶与~ 21 ″鸟嘌呤核苷酸交换蛋白的接头蛋白）、胞质酪氨酸激酶如c-Fyn和c-Src以及可能在各种细胞背景中的其它SH 2蛋白相关。据推测，这些生长因子的特征性生物反应是由相互作用的SH 2蛋白的精确组合引起的（5）。胰岛素受体采用了该模型的一个有趣的变体。胰岛素受体自身磷酸化刺激激酶活性，但与EGF和PDGF受体不同，胰岛素受体似乎与SH 2蛋白没有直接联系。相反，激活的胰岛素受体磷酸化IRS-1，胰岛素受体的主要底物，在多个酪氨酸残基上，其反过来识别并结合SH 2-
In mammals, insulin is the principal hormone controlling blood glucose and acts by stimulating glucose influx and metabolism in muscle and adipocytes and inhibiting gluconeogenesis by the liver. In addition, insulin modifies the expression or activity of a variety of enzymes and transport systems in nearly all cels. Insulin action is mediated through the insulin receptor, a transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. The level of tyrosine kinase activity reflects the serum concentration of insulin and appears to mediate the insulin response through tyrosine phosphorylation of the receptor itself and substrates like insulin recep-tor substrate-1 (IRS-l). l Non-insulin-dependent diabetes mellitus is due in large part to insulin resistance, a state when the target cells no longer respond to ordinary levels of circulating insulin. To understand the mechanisms of control of normal metabolism, as well as the pathogenesis of non-insulin-dependent diabetes mellitus, it is critical to understand the signaling pathways used by the insulin receptor.Many plasma membrane receptors regulate cellular processes through protein tyrosine kinases. The receptor for insulin, like the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), contains intrinsic tyrosine kinase activity (1). The antigen receptor on T and B cells, as well as receptors for growth hormone, erythropoietin, and several cytokines, do not have intrinsic tyrosine kinase activity but stimulate tyrosine phosphorylation by association with cytoplasmic tyrosine kinases like Fyn, Tyk-2, or Jak-1 and-2 (2, 3). In each case, ligand binding activates the associated tyrosine kinases, and for the receptor tyrosine ki-nases most evidence indicates that this step is essential for biological activity. The activated receptors frequently undergo autophosphorylation on tyrosine residues in the cytoplasmic domain. To propagate the signal, many autophosphorylated receptors bind directly to proteins containing Src homology 2 domains (SH2 proteins). The binding of SH2 proteins depends on the amino acid sequence surrounding the tyrosine autophosphorylation site in each receptor (4). EGF and PDGF receptors associate to varying degrees with phosphatidylinositol (PI) 3'-kinase, p2lm"-GAP, phospholipase Cy, GRB-2 (an adapter protein that links tyrosine ki-nases to a~ 2 1~" guanine nucleotide exchange protein), cytoplasmic tyrosine kinases like c-Fyn and c-Src, and probably other SH2 proteins in various cellular backgrounds. Presumably, the characteristic biological response of these growth factors results from the exact combination of interacting SH2 proteins (5). An interesting variation of this model is employed by the insulin receptor. Insulin receptor autophosphorylation stimulates kinase activity, but unlike the EGF and PDGF receptors, the insulin receptor does not appear to have direct associations with SH2 proteins. In contrast, the activated insulin receptor phosphorylates IRS-1, a principle substrate of the insulin receptor, on multiple tyrosine residues, which in turn recognize and bind to the SH2-