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的可用性，最显著的是氨基酸。并入mTORC 1复合物中，mTOR通过定位于溶酶体膜的胞质小叶的调节网络感测氨基酸的可用性。失调的mTOR信号传导有助于人类疾病如癌症和糖尿病的进展。我们已经获得了强有力的初步数据，通过mTORC1的溶酶体氨基酸传感依赖于内体逆转录酶复合物。Retromer是一种进化保守的多蛋白复合物，存在于晚期内体上，并组织广泛的整合膜蛋白的再循环。该提案要求提供资金来研究retromer如何通过mTOR促进氨基酸信号传导的机制基础。 要做到这一点，我们建议使用各种各样的蛋白质组学和细胞生物学方法来研究在哪个阶段，以及为什么氨基酸信号通过mTORC 1失败的逆转录酶缺陷的细胞系，我们已经产生了这个项目。

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.