TY - JOUR
T1 - mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate
AU - Marat, Andrea L.
AU - Wallroth, Alexander
AU - Lo, Wen Ting
AU - Müller, Rainer
AU - Norata, Giuseppe Danilo
AU - Falasca, Marco
AU - Schultz, Carsten
AU - Haucke, Volker
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/6/2
Y1 - 2017/6/2
N2 - 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.
AB - 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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U2 - 10.1126/science.aaf8310
DO - 10.1126/science.aaf8310
M3 - Article
C2 - 28572395
AN - SCOPUS:85020306218
SN - 0036-8075
VL - 356
SP - 968
EP - 972
JO - Science
JF - Science
IS - 6341
ER -