INSULIN-RECEPTOR INTERNALIZATION - MOLECULAR MECHANISMS AND PHYSIOPATHOLOGICAL IMPLICATIONS
INSULIN-RECEPTOR INTERNALIZATION - MOLECULAR MECHANISMS AND PHYSIOPATHOLOGICAL IMPLICATIONS
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DOI：
10.1007/bf00400835
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发表时间：
1994-09-01
期刊：
影响因子：
8.2
通讯作者：
CARPENTIER, JL
中科院分区：
文献类型：
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作者：
CARPENTIER, JL
胰岛素与靶细胞表面受体之间的初始相互作用之后是参与胰岛素作用控制的一系列表面和细胞内步骤。这些步骤中的任何一个的缺失都可能导致受体的错误处理，从而导致细胞表面上受体数量的调节缺陷和细胞对激素的不适当敏感性。因此，识别这些步骤中的每一个以及理解控制它们的机制对于揭示胰岛素抵抗状态的发病机制的某些方面是必要的。这是我们近年来使用分子和细胞生物学以及生物化学技术进行研究的目标。这些研究使我们能够提出以下有序的事件序列：1）胰岛素优先与细胞表面微绒毛相关的受体结合; 2）胰岛素触发受体激酶激活和自磷酸化，这不仅导致胰岛素作用的各种生物信号的启动，而且导致胰岛素-受体复合物在膜平面中的重新分布; 3）在细胞表面的非绒毛结构域上，胰岛素受体通过存在于其胞质质膜结构域中的特异性“内化序列”锚于网格蛋白包被的小凹; 4）胰岛素-受体复合物与存在于相同网格蛋白包被的小凹中的其它受体一起内化，形成网格蛋白包被的囊泡; 5）复合物被递送至内体，内体的酸性pH诱导胰岛素分子从胰岛素受体解离并以不同方向分选; 6）胰岛素分子被靶向至晚期内体和溶酶体，在那里它们被降解; 7）受体被再循环回到细胞表面以便再利用。
The initial interaction between insulin and its receptor on target cell surface is followed by a series of surface and intracellular steps which participate in the control of insulin action. Abnormalities of any of these steps could result in mishandling of the receptor leading to defective modulation of receptor number on the cell surface and to inappropriate cell sensitivity to the hormone. Thus, the identification of each of these steps as well as understanding the mechanisms governing them is obligatory to unravel some aspects of the pathogenesis of insulin resistance states. This was the goal of the studies we have carried out during recent years using combined molecular and cellular biology as well as biochemical techniques. These studies allowed us to propose the following ordered sequence of events: 1) insulin binds to receptors preferentially associated with microvilli on the cell surface; 2) insulin triggers receptor kinase activation and autophosphorylation which not only results in initiation of the various biological signals leading to insulin action but also in redistribution of the hormone-receptor complex in the plane of the membrane; 3) on the non-villous domain of the cell surface, insulin receptors anchor to clathrin-coated pits through specific ''internalization sequences'' present in their cytoplasmic juxtamembrane domain; 4) insulin-receptor complexes are internalized together with other receptors present in the same clathrin-coated pits through the formation of clathrin-coated vesicles; 5) the complexes are delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions; 6) insulin molecules are targetted to late endosomes and lysosomes where they are degraded; 7) receptors are recycled back to the cell surface in order to be reused.