Regulation of Akt Signaling by Detergent Resistant Membrane Associated Protein ClipR-59

项目摘要 丝氨酸/苏氨酸蛋白激酶Akt是胰岛素代谢作用的中心介质。Akt活性受损导致 II型糖尿病是一种地球仪大流行病，在可预见的未来仍将是公共卫生的主要挑战。一 Akt参与代谢作用的主要机制是促进葡萄糖转运， 脂肪和肌肉细胞，这一过程需要Akt膜区室化。我们的研究是 了解Akt膜区室化是如何调节的。为此，我们将ClipR-59确定为一种 调节Akt膜区室化，并证明，通过调节Akt膜 ClipR-59调节胰岛素依赖性Glut 4膜转位，并且ClipR-59 ClipR-59在小鼠体内的转基因表达对葡萄糖和能量代谢起调节作用 脂肪组织降低血糖水平，增加糖耐量，并导致小鼠对抗饮食诱导的 肥胖目前的建议是我们继续努力，以确定ClipR-59在整个监管中的作用。 体内葡萄糖稳态和ClipR-59调节Akt信号传导的机制。我们的假设 ClipR-59的失活将导致身体葡萄糖和能量代谢的失调，而Elmo 2 和DHHC 17，通过它们调节Akt与ClipR-59的相互作用和ClipR-59与 抗洗涤剂膜，是Akt膜区室化的新调节剂。我们特别 将确定a）脂肪组织中ClipR-59的可诱导失活如何影响葡萄糖稳态， 肥胖的发展; B）支架蛋白Elmo 2如何通过其胰岛素调节与ClipR-59的相互作用， 调节Akt膜区室化和胰岛素依赖性Glut 4膜易位，和c） 半胱氨酸棕榈酰酰基转移酶DHHC 17如何通过调节ClipR-59棕榈酰化和去污剂 耐药膜（DRM）协会，调节Akt膜区室化。总体而言，我们 应用将使我们能够进一步确定ClipR-59在Akt信号转导和整个身体调节中的作用。 葡萄糖稳态和ClipR-59调节这些过程的分子机制。我们 我相信，成功地执行我们的建议，无疑将促进我们对监管的理解， 胰岛素信号传导与II型糖尿病的发生。

Project Summary Ser/Thr protein kinase Akt is a central mediator of insulin metabolic action. Impairment in Akt activity results in type II diabetes, a globe pandemic that will remain major challenges to public health in foreseeable future. A primary mechanism under which Akt to participate in metabolic action is to promote glucose transport in adipose and muscle cells, a process that is requires Akt membrane compartmentalization. Our studies is to understand how Akt membrane compartmentalization is regulated. To such goal, we identified ClipR-59 as a regulator of Akt membrane compartmentalization and demonstrated that, by modulating Akt membrane compartmentalization, ClipR-59 regulates insulin dependent Glut4 membrane translocation and that ClipR-59 plays a role in the regulation of glucose and energy metabolism as transgenic expression of ClipR-59 in mouse adipose tissue lowered blood glucose level, increased glucose tolerance and led the mice against diet induced obesity. The current proposal is our continued effort to define the role of ClipR-59 in the regulation of whole body glucose homeostasis and the mechanism under which ClipR-59 regulates Akt signaling. Our hypothesis is that inactivation of ClipR-59 will lead to dysregulation of body glucose and energy metabolism, and Elmo2 and DHHC17, via their regulations of the interaction of Akt with ClipR-59 and ClipR-59 association with detergent resistant membrane, are the new regulators of Akt membrane compartmentalization. Specifically, we will determine a) how inducible inactivation of ClipR-59 in adipose tissue affects glucose homeostasis and the development of obesity; b) how scaffold protein Elmo2, through its insulin regulated interaction with ClipR-59, regulates Akt membrane compartmentalization and insulin dependent Glut4 membrane translocation and c) how cysteine palmitoyl acyltransferase DHHC17, through modulating ClipR-59 palmitoylation and detergent resistant membrane (DRM) association, regulates Akt membrane compartmentalization. Overall, our application will allow us further define the role of ClipR-59 in the regulation of Akt signaling and whole body glucose homeostasis and the molecular mechanism under which ClipR-59 regulates these processes. We believe successful conducting our proposal will undoubtedly advance our understanding of the regulation of insulin signaling and the development of type II diabetes.