| Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation. | |
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MedLine Citation:
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PMID: 20498635 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The phosphoinositide3-kinase (PI3K)/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signalling cascades promote normal growth and are frequently hyperactivated in tumour cells. mTORC1 is also regulated by local nutrients, particularly amino acids, but the mechanisms involved are poorly understood. Unexpectedly, members of the proton-assisted amino-acid transporter (PAT or SLC36) family emerged from in vivo genetic screens in Drosophila as transporters with uniquely potent effects on mTORC1-mediated growth. In this study, we show the two human PATs that are widely expressed in normal tissues and cancer cell lines, namely PAT1 and PAT4, behave similarly to fly PATs when expressed in Drosophila. Small interfering RNA knockdown shows that these molecules are required for the activation of mTORC1 targets and for proliferation in human MCF-7 breast cancer and HEK-293 embryonic kidney cell lines. Furthermore, activation of mTORC1 in starved HEK-293 cells stimulated by amino acids requires PAT1 and PAT4, and is elevated in PAT1-overexpressing cells. Importantly, in HEK-293 cells, PAT1 is highly concentrated in intracellular compartments, including endosomes, wherein mTOR shuttles upon amino-acid stimulation. Therefore our data are consistent with a model in which PATs modulate the activity of mTORC1 not by transporting amino acids into the cell but by modulating the intracellular response to amino acids. |
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Authors:
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S Heublein; S Kazi; M H Ogmundsdóttir; E V Attwood; S Kala; C A R Boyd; C Wilson; D C I Goberdhan |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-24 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-15 Completed Date: 2010-08-10 Revised Date: 2011-07-20 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 4068-79 Citation Subset: IM |
Affiliation:
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Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Transport Systems
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physiology* Amino Acids / physiology* Cell Line, Tumor Cell Proliferation* Humans Protons Transcription Factors / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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A6174//Cancer Research UK; A6181//Cancer Research UK; A9093//Cancer Research UK; C191591/A6181//Canadian Institutes of Health Research; C19591/A9093//Cancer Research UK; C7713/A6174//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Transport Systems; 0/Amino Acids; 0/Protons; 0/Transcription Factors; 0/mTORC1 complex, human |
| Comments/Corrections | |
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