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。激活的受体使多种细胞内蛋白质中的酪氨酸残基磷酸化。我们研究了GLUT4葡萄糖转运体在分离的大鼠脂肪细胞中将葡萄糖转运蛋白转移到质膜的下游途径，脂肪细胞是胰岛素作用的重要生理靶细胞。利用大鼠脂肪细胞瞬时表达技术，我们已经证明IRS-1是参与介导胰岛素对GLUT4转位作用的底物之一，而磷脂酰肌醇3-激酶(PI-3-Kinase)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，我们在以下几个方面扩展了这些研究：(1)研究IRS-3与受体酪氨酸激酶及其下游信号分子的相互作用；(2)克隆和鉴定果蝇中一种新的胰岛素受体底物蛋白。此外，我们已经开始研究确定IRS蛋白的亚细胞定位，并确定负责将IRS靶向到其在细胞内的正常位置的序列。-胰岛素，酪氨酸激酶，胰岛素受体底物，脂肪组织，葡萄糖转运，分类连接蛋白，空泡蛋白分类

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. - insulin, tyrosine kinase, insulin receptor substrate, adipose tissue, glucose transport, sorting nexin, vacuolar protein sorting