title: PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids.
abstract: Growth in normal and tumour cells is regulated by evolutionarily conserved extracellular inputs from the endocrine insulin receptor (InR) signalling pathway and by local nutrients. Both signals modulate activity of the intracellular TOR kinase, with nutrients at least partly acting through changes in intracellular amino acid levels mediated by amino acid transporters. We show that in Drosophila, two molecules related to mammalian proton-assisted SLC36 amino acid transporters (PATs), CG3424 and CG1139, are potent mediators of growth. These transporters genetically interact with TOR and other InR signalling components, indicating that they control growth by directly or indirectly modulating the effects of TOR signalling. A mutation in the CG3424 gene, which we have named pathetic (path), reduces growth in the fly. In a heterologous Xenopus oocyte system, PATH also activates the TOR target S6 kinase in an amino acid-dependent way. However, functional analysis reveals that PATH has an extremely low capacity and an exceptionally high affinity compared with characterised human PATs and the CG1139 transporter. PATH and potentially other PAT-related transporters must therefore control growth via a mechanism that does not require bulk transport of amino acids into the cell. As PATH is likely to be saturated in vivo, we propose that one specialised function of high-affinity PAT-related molecules is to maintain growth as local nutrient levels fluctuate during development.
authors.affiliation: Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. deborah.goberdhan@anat.ox.ac.uk
authors.forename: Deborah C I
authors.initials: DC
authors.lastname: Goberdhan
authors.forename: David
authors.initials: D
authors.lastname: Meredith
authors.forename: C A Richard
authors.initials: CA
authors.lastname: Boyd
authors.forename: Clive
authors.initials: C
authors.lastname: Wilson
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western; D048708:Cell Growth Processes / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014921:Wings, Animal / Q000033:anatomy & histology; D014981:Xenopus
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D029721:Drosophila Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C502708:path protein, Drosophila; C416303:target of rapamycin protein, Drosophila; C094982:InR protein, Drosophila