INSULIN RECEPTORS AND MOLECULAR MECHANISMS OF INSULIN ACTION

胰岛素与靶细胞表面的受体结合，从而激活胰岛素受体酪氨酸激酶。被激活的受体磷酸化多种细胞内蛋白中的酪氨酸残基。我们研究了分离大鼠脂肪细胞中GLUT4葡萄糖转运蛋白向质膜转运的下游途径，这是胰岛素作用的生理重要靶细胞。利用在大鼠脂肪细胞中瞬时表达的技术，我们已经证明IRS-1是参与介导胰岛素对GLUT4转运作用的底物之一，磷脂酰肌醇3-激酶（PI 3-激酶）活性的激活也在介导胰岛素的这一作用中起着必要的作用。最近，我们从几个方面扩展了这些研究：(1)表征IRS-3与受体酪氨酸激酶以及下游信号分子的相互作用；(2)果蝇胰岛素受体底物蛋白的克隆与鉴定。此外，我们已经开始研究IRS蛋白的亚细胞定位，并确定了IRS靶向到细胞内正常位置的序列。

Insulin binds to its receptor on the surface of the target cell, thereby activating the insulin receptor tyrosine kinase. The activated receptor phosphorylates tyrosine residues in multiple intracellular proteins. We have investigated the downstream pathway that eventuates in translocation of GLUT4 glucose transporters to the plasma membrane in isolated rat adipocytes, a physiologically important target cell for insulin action. Using an technique involving transient expression in rat adipocytes, we have previously demonstrated that IRS-1 is one of the substrates which participates in mediating the effect of insulin to translocate GLUT4, and that activation of phosphatidyl inositol 3-kinase (PI 3-kinase) activity also plays a necessary role in mediating this action of insulin. Recently, we have extended these studies in several ways: (1) characterizing interactions of IRS-3 with receptor tyrosine kinases and also with downstream signaling molecules; (2) cloning and characterization of a novel insulin receptor substrate protein in Drosophila. In addition, we have initiated studies to define the subcellular localization of IRS proteins, and also to define the sequences that are responsible for targeting of IRS to its normal location within the cell.