Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes
| Autor: | Bruno Reynolds, Deborah C.I. Goberdhan, Sabine Heublein, Michael K. Shaw, Margret H. Ogmundsdottir, Shubana Kazi, Shivanthy M. Visvalingam |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Macromolecular Assemblies
Amino Acid Transport Systems Tumor Physiology Gene Identification and Analysis lcsh:Medicine GTPase mTORC1 Biochemistry Intracellular Receptors GTP Phosphohydrolases Transmembrane Transport Proteins Phosphatidylinositol 3-Kinases Signal Initiation Endocrinology Insulin Signaling Cascade Molecular Cell Biology Basic Cancer Research Signaling in Cellular Processes Insulin Amino Acids lcsh:Science Insulin-like Growth Factor Protein Metabolism Multidisciplinary Symporters biology Drosophila Melanogaster TOR Serine-Threonine Kinases Mechanisms of Signal Transduction Animal Models Ragulator complex Signaling Cascades Endocytosis Cell biology Oncology Medicine Female Transmembrane Signaling Research Article Signal Transduction Protein Binding RHEB Proto-Oncogene Proteins c-akt Endosome Endosomes Mechanistic Target of Rapamycin Complex 1 Signaling Pathways Cell Growth Molecular Genetics Model Organisms Growth Factors Genetics Cancer Genetics Akt Signaling Cascade Animals Humans Amino acid transporter Protein Interactions Biology PI3K/AKT/mTOR pathway Monomeric GTP-Binding Proteins Endocrine Physiology Neuropeptides lcsh:R Proteins Intracellular Membranes Metabolism HEK293 Cells Multiprotein Complexes Genetics of Disease biology.protein Ras Homolog Enriched in Brain Protein lcsh:Q Gene Function Lysosomes Tor Signaling Developmental Biology Insulin-Dependent Signal Transduction |
| Zdroj: | PLoS ONE, Vol 7, Iss 5, p e36616 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Mammalian Target of Rapamycin Complex 1 (mTORC1) is activated by growth factor-regulated phosphoinositide 3-kinase (PI3K)/Akt/Rheb signalling and extracellular amino acids (AAs) to promote growth and proliferation. These AAs induce translocation of mTOR to late endosomes and lysosomes (LELs), subsequent activation via mechanisms involving the presence of intralumenal AAs, and interaction between mTORC1 and a multiprotein assembly containing Rag GTPases and the heterotrimeric Ragulator complex. However, the mechanisms by which AAs control these different aspects of mTORC1 activation are not well understood. We have recently shown that intracellular Proton-assisted Amino acid Transporter 1 (PAT1)/SLC36A1 is an essential mediator of AA-dependent mTORC1 activation. Here we demonstrate in Human Embryonic Kidney (HEK-293) cells that PAT1 is primarily located on LELs, physically interacts with the Rag GTPases and is required for normal AA-dependent mTOR relocalisation. We also use the powerful in vivo genetic methodologies available in Drosophila to investigate the regulation of the PAT1/Rag/Ragulator complex. We show that GFP-tagged PATs reside at both the cell surface and LELs in vivo, mirroring PAT1 distribution in several normal mammalian cell types. Elevated PI3K/Akt/Rheb signalling increases intracellular levels of PATs and synergistically enhances PAT-induced growth via a mechanism requiring endocytosis. In light of the recent identification of the vacuolar H+-ATPase as another Rag-interacting component, we propose a model in which PATs function as part of an AA-sensing engine that drives mTORC1 activation from LEL compartments. © 2012 Ögmundsdóttir et al. |
| Databáze: | OpenAIRE |
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