Figure 7.

A model to explain the effects of the PATs on mTORC1 signalling and proliferation. We have shown that PATs modulate the response of mTORC1 to extracellular amino acids in HEK-293 cells, even though one of the critical PATs in this process, PAT1, is concentrated intracellularly. We propose that these intracellular PATs are likely to affect mTORC1 signalling in late endosomes to which mTOR is shuttled upon amino acid stimulation. They may act via a transport-dependent or transceptor mechanism, forming a complex with other mTOR regulatory proteins, or they may be components of one of a series of endosomal complexes involved in this process. Cytoplasmic leucine, which activates S6K1, may bind to the cytoplasmic face of the PATs to enhance their ability to activate mTORC1. Rag GTPases are required to shuttle mTOR to Rheb-containing endosomal compartments upon amino acid stimulation, but evidence in yeast suggests they may also bind to amino acid transporters and promote their shuttling. Rag-dependent shuttling of PATs to the endosomes may therefore be a critical aspect of mTOR regulation.