INSULIN-INDUCED TRANSLOCATION OF GLUCOSE TRANSPORTER

描述（摘自申请人摘要） 胰岛素通过刺激肌肉在葡萄糖稳态中起重要作用 和脂肪细胞来摄取葡萄糖。胰岛素是通过激活一种信号 在葡萄糖转运蛋白GLUT 4的募集中达到高潮的途径 从细胞内区室到细胞表面。该途径 显然涉及磷脂酰肌醇3-激酶（PI）的激活 3-激酶）。然而，PI 3-激酶的信号转导靶点仍不清楚， 并且使GLUT 4移位的效应器机制仍然是难以捉摸的。 这种胰岛素信号通路具有重要的医学意义，因为 它的损伤可能会导致肥胖、糖尿病、 多囊卵巢综合征的长期目标 申请人需要从分子角度理解胰岛素如何起作用。等 这些知识可能会产生治疗上述疾病的新方法。 申请人建议在培养脂肪中解决以下问题 细胞： 1.胰岛素诱导的GLUT 4易位是否涉及通过 PI 3-激酶是其拟靶点，如蛋白激酶B及其亚型 蛋白激酶C这些动力学的作用将由 激活或阻断它们，并观察对GLUT 4的影响 易位 2.胰岛素诱导的GLUT 4易位是否可以用一种假定的 细胞内GLUT 4伴侣？该分子伴侣可用于锚GLUT 4 在没有胰岛素的情况下在细胞内。在胰岛素的存在下， 伴侣蛋白会释放GLUT 4，并允许它跟随胞吐流， 细胞表面为了克隆这种假定的伴侣，提出了两种策略。 3.胰岛素诱导的GLUT 4易位是否涉及GLUT 4的分选 组装成网格蛋白包被的囊泡？AP与 其他具有与GLUT 4相似的分选基序的蛋白质，并将它们分选为 网格蛋白包被的囊泡。这些囊泡被认为是介导 GLUT 4易位。AP在GLUT 4贩运中的作用将是 通过确定AP是否与GLUT 4相互作用以及 相互作用由胰岛素调节。

DESCRIPTION (Taken from the applicant's Abstract) Insulin plays an important role in glucose homeostasis by stimulating muscle and fat cells to take up glucose. Insulin does so by activating a signaling pathway that culminates in the recruitment of the glucose transporter GLUT4 from an intracellular compartment to the cell surface. This pathway apparently involves the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the signaling target of PI 3-kinase remains unclear, and the effector machinery that translocates GLUT4 remains elusive. This insulin signaling pathway has significant medical implications, since its impairment may contribute to the development of obesity, diabetes mellitus, and polycystic ovarian syndrome. The long-term objective of the applicant is to understand in molecular terms how insulin works. Such knowledge may engender new treatments for the aforementioned diseases. The applicant proposes to address the following questions in cultured fat cells: 1. Does insulin-induced GLUT4 translocation involve the activation by PI 3-kinase of its proposed targets, such as protein kinase B and isoforms of protein kinase C? The role of these kineses will be investigated by activating or blocking them and observing the resultant effect on GLUT4 translocation. 2. Can insulin-induced GLUT4 translocation be explained by a putative intracellular GLUT4 chaperon? This chaperon would serve to anchor GLUT4 intracellularly in the absence of insulin. In the presence of insulin, the chaperon would release GLUT4 and allow it to follow the exocytic flow toward cell surface. To clone this putative chaperon, two strategies are proposed. 3. Does insulin-induced GLUT4 translocation involve sorting of GLUT4 into clathrin-coated vesicles by assembly proteins (APs)? APs interact with other proteins bearing similar sorting motifs as GLUT4, and sort them into clathrin-coated vesicles. These vesicles have been proposed to mediate GLUT4 translocation. The role of APs in GLUT4 trafficking will be investigated by determining if APs interact with GLUT4 and if the interaction is modulated by insulin.