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

    Access Status
    Fulltext not available
    Authors
    Marat, A.
    Wallroth, A.
    Lo, W.
    Müller, R.
    Norata, G.
    Falasca, Marco
    Schultz, C.
    Haucke, V.
    Date
    2017
    Type
    Journal Article
    
    Metadata
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    Citation
    Marat, A. and Wallroth, A. and Lo, W. and Müller, R. and Norata, G. and Falasca, M. and Schultz, C. et al. 2017. mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. Science. 356 (6341): pp. 968-972.
    Source Title
    Science
    DOI
    10.1126/science.aaf8310
    ISSN
    0036-8075
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/54003
    Collection
    • Curtin Research Publications
    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 b (PI3KC2b) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2b hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2b 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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