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

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Science  02 Jun 2017:
Vol. 356, Issue 6341, pp. 968-972
DOI: 10.1126/science.aaf8310

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Local specificity of growth signals

The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth in response to nutrients. Marat et al. found that the lipid phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], which, when generated at the cell surface, is linked to stimulation of mTORC1 and promotion of cell growth, does the opposite when synthesized at the late endosome or lysosome. In cells deprived of nutrients, PI(3,4)P2 was produced at lysosomes, where it recruited an inhibitor of mTORC1. The results elucidate the complex regulation of mTORC1, which is altered in human diseases such as cancer and neurodegeneration.

Science, this issue p. 968


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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