INSULIN-INDUCED TRANSLOCATION OF GLUCOSE TRANSPORTER

胰岛素诱导的葡萄糖转运蛋白易位

• 批准号: 2443782
• 负责人: NAI-WEN CHI
• 金额: $ 8.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443782
• 关键词: 3T3 cells; adipocytes; biological signal transduction; clathrin; enzyme activity; exocytosis; glucose transporter; hormone regulation /control mechanism; insulin; intermolecular interaction; intracellular transport; membrane proteins; molecular chaperones; molecular cloning; phosphatidylinositol 3 kinase; protein transport

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.

描述（摘自申请人的摘要） 胰岛素通过刺激肌肉在葡萄糖稳态中发挥重要作用 和脂肪细胞吸收葡萄糖。胰岛素通过激活信号传导来做到这一点 最终募集葡萄糖转运蛋白 GLUT4 的途径 从细胞内区室到细胞表面。这条路 显然涉及磷脂酰肌醇 3-激酶 (PI 3-激酶）。然而，PI 3-激酶的信号传导靶点仍不清楚， 而转运 GLUT4 的效应器机制仍然难以捉摸。 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、糖尿病的发生 以及多囊卵巢综合症。该组织的长期目标 申请人将从分子角度理解胰岛素如何发挥作用。这样的 知识可能会产生针对上述疾病的新疗法。 申请人建议解决培养脂肪中的以下问题 细胞： 1. 胰岛素诱导的GLUT4易位是否涉及激活 其提议靶标的 PI 3-激酶，例如蛋白激酶 B 和亚型 蛋白激酶C？这些运动的作用将通过以下方式进行研究 激活或阻止它们并观察对 GLUT4 的最终影响 易位。 2. 胰岛素诱导的 GLUT4 易位能否用假定的解释来解释？ 细胞内GLUT4伴侣？该伴侣将用于锚定 GLUT4 在没有胰岛素的情况下在细胞内。在胰岛素存在的情况下， 伴侣会释放 GLUT4 并允许其跟随胞吐流向 细胞表面。为了克隆这个假定的伴侣，提出了两种策略。 3. 胰岛素诱导的GLUT4易位是否涉及GLUT4的分选 通过组装蛋白（AP）进入网格蛋白包被的囊泡中？ AP 交互 其他具有与 GLUT4 类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。这些囊泡被认为可以介导 GLUT4易位。 AP 在 GLUT4 贩运中的作用将是 通过确定 AP 是否与 GLUT4 相互作用以及是否 相互作用受胰岛素调节。