A42
Members of the Proton-Assisted Amino Acid Transporter (PAT/SLC36) family are located in intracellular endosomal compartments that locally activate S6-kinase
Deborah Goberdhan, Margret Ogmundsdottir, Shivanthy Visvalingam, Bruno Reynolds, Shubana Kazi, Richard Boyd, Clive Wilson
University of Oxford, Oxford, UK
Studies in Drosophila have been instrumental in demonstrating a link between the PI3-kinase/Akt signalling cassette and the TOR signalling cascade. This pathway is frequently hyperactivated in a broad range of human cancers. More recent work in flies has shown that members of the Proton-Assisted (PAT/SLC36) class of amino acid transporters have uniquely potent effects on TOR-mediated growth. However, the mechanisms by which PATs interact with TOR have not yet been characterised.
Using genetic analysis in the fly eye, we show here that the growth-promoting effects of the PATs are dramatically enhanced when PI3K/Akt signalling is increased through recessive PTEN mutation, a defect which is commonly observed in human cancers. Furthermore, in vivo analysis in the fly and also in cell culture has shown that the PATs are located both at the cell surface and in intracellular endosomal and lysosomal compartments and that their distribution is modulated by PI3K/Akt signalling. We show that intracellular compartments containing the PATs locally activate the TOR downstream target S6-kinase. We propose that activation of TOR signalling via intracellular amino acid transporters may enable tumour cells to take advantage of intracellular nutrient stores, particularly in nutrient- and growth factor-depleted conditions, where these cells show a strong growth advantage over normal cells.
