Retromer maintains amino acid signaling through mTORC1

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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.