Retromer maintains amino acid signaling through mTORC1

mTOR激酶协调真核细胞的生长和代谢与生长因子和营养物质的可用性，最显著的是氨基酸。与mTORC1复合物结合后，mTOR通过定位于溶酶体膜的胞质小叶的调节网络感知氨基酸的可用性。解除对mTOR信号的调控有助于癌症和糖尿病等人类疾病的进展。我们已经获得了强有力的初步数据，通过mTORC1的溶酶体氨基酸感应依赖于内体反转录复合物。逆转录酶是一种进化保守的多蛋白复合物，位于内体晚期，并组织广泛的整体膜蛋白的再循环。该提案要求资助研究逆转录物如何通过mTOR促进氨基酸信号传导的机制基础。为此，我们建议使用多种蛋白质组学和细胞生物学方法来研究在我们为该项目生成的逆转录酶缺陷细胞系中，通过mTORC1的氨基酸信号传导在哪个阶段以及为什么失败。

The mTOR kinase coordinates the growth and the metabolism of eukaryotic cells with the availability of growth factors and nutrients, most notably of amino acids. Incorporated into the mTORC1 complex, mTOR senses the availability of amino acids through a regulatory network that is localized to the cytosolic leaflet of the lysosomal membrane. Deregulated mTOR signaling contributes to the progression of human diseases such as cancer and diabetes. We have obtained strong preliminary data that lysosomal amino acid sensing through mTORC1 depends on the endosomal retromer complex. Retromer is an evolutionary conserved multi-protein complex that resides on late endosomes and organizes recycling of a wide range of integral membrane proteins. This proposal asks for funding to investigate the mechanistic basis of how retromer promotes amino acid signaling through mTOR. To do so, we propose to use a wide variety of proteomic and cell biological methods to investigate at which stage and why amino acid signaling through mTORC1 fails in the retromer deficient cell lines that we have generated for this project.