Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation

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...

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Published in:	Oncogene Vol. 29; no. 28; pp. 4068 - 4079
Main Authors:	Heublein, S, Kazi, S, Ögmundsdóttir, M H, Attwood, E V, Kala, S, Boyd, C A R, Wilson, C, Goberdhan, D C I
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15-07-2010 Nature Publishing Group
Subjects:	1-Phosphatidylinositol 3-kinase 631/136/2091 631/45/612/1222 631/67 631/80/86 AKT protein Amino Acid Transport Systems - physiology Amino acids Amino Acids - physiology Apoptosis Biological and medical sciences Breast cancer Cancer Cell activation Cell Biology Cell growth Cell Line, Tumor Cell physiology Cell Proliferation Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular signal transduction Drosophila Endosomes Fundamental and applied biological sciences. Psychology Gene expression Genetic aspects Genetic screening Human Genetics Humans Insects Internal Medicine Intracellular Kinases Mechanistic Target of Rapamycin Complex 1 Medicine Medicine & Public Health Molecular and cellular biology Multiprotein Complexes Oncology original-article Physiological aspects Protein kinases Proteins Protons Rapamycin siRNA TOR protein TOR Serine-Threonine Kinases Transcription Factors - physiology Tumor cell lines Tumors United Kingdom Germany SLC36 PAT amino-acid sensing transceptor mTORC1 transporter Cell proliferation Biological transport Proton Activation Carcinogenesis
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S Heublein and S Kazi contributed equally to this work. present address: Institut für Zelluläre und Molekulare Physiologie, Universität Erlangen-Nürnberg, Waldstraße 6 D-91054 Erlangen, Germany present address: D3 Technologies, Nova Technology Park, 5 Robroyston Oval, Glasgow G33 1AP, UK
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2010.177