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Science. 2017 Jun 2;356(6341):968-972. doi: 10.1126/science.aaf8310.

mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate.

Author information

1
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
2
European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany.
3
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
4
Curtin Health Innovation Research Institute, School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
5
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Roessle-Strasse 10, 13125 Berlin, Germany. haucke@fmp-berlin.de.

Abstract

Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], synthesized by class II PI3K β (PI3KC2β) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2β hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2β with the Raptor subunit of mTORC1. Local PI(3,4)P2 synthesis triggered repression of mTORC1 activity through association of Raptor with inhibitory 14-3-3 proteins. These results unravel an unexpected function for local PI(3,4)P2 production in shutting off mTORC1.

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PMID:
28572395
DOI:
10.1126/science.aaf8310
[Indexed for MEDLINE]

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