Retromer maintains amino acid signaling through mTORC1

MTOR激酶通过生长因子和营养物质的可获得性来协调真核细胞的生长和新陈代谢，尤其是氨基酸。结合到mTORC1复合体中，mTOR通过定位于溶酶体膜胞质小叶的调节网络来感知氨基酸的可用性。去调控的mTOR信号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，即通过mTORC1来感知溶酶体氨基酸依赖于内体逆转聚体复合体。逆转录聚体是一种进化保守的多蛋白质复合体，存在于晚期的内吞体内，并组织一系列完整的膜蛋白的循环。这项提案要求提供资金，以研究逆转录病毒如何通过mTOR促进氨基酸信号传递的机制基础。为此，我们建议使用各种蛋白质组学和细胞生物学方法来调查在哪个阶段，以及为什么在我们为该项目产生的逆转录病毒缺陷细胞系中，通过mTORC1的氨基酸信号传递失败。

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.