Document Detail


Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation.
MedLine Citation:
PMID:  20498635     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-24
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-15     Completed Date:  2010-08-10     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  4068-79     Citation Subset:  IM    
Affiliation:
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Transport Systems / physiology*
Amino Acids / physiology*
Cell Line, Tumor
Cell Proliferation*
Humans
Proteins
Protons
Transcription Factors / physiology*
Grant Support
ID/Acronym/Agency:
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:
0/Amino Acid Transport Systems; 0/Amino Acids; 0/Proteins; 0/Protons; 0/Transcription Factors; 0/mechanistic target of rapamycin complex 1
Comments/Corrections

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