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

Andrea L. Marat, Alexander Wallroth, Wen Ting Lo, Rainer Müller, Giuseppe Danilo Norata, Marco Falasca, Carsten Schultz, Volker Haucke

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)968-972
Number of pages5
JournalScience
Volume356
Issue number6341
DOIs
StatePublished - Jun 2 2017
Externally publishedYes

Fingerprint

Raptors
Endosomes
Class II Phosphatidylinositol 3-Kinases
Lysosomes
Class I Phosphatidylinositol 3-Kinases
Intercellular Signaling Peptides and Proteins
14-3-3 Proteins
mechanistic target of rapamycin complex 1
phosphatidylinositol 3,4-diphosphate
Cell Membrane
Food
Growth
phosphoinositide-3,4-bisphosphate
phosphoinositide-3,4,5-triphosphate
phosphatidylinositol 3,4,5-triphosphate

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Marat, A. L., Wallroth, A., Lo, W. T., Müller, R., Norata, G. D., Falasca, M., ... Haucke, V. (2017). mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. Science, 356(6341), 968-972. https://doi.org/10.1126/science.aaf8310

mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. / Marat, Andrea L.; Wallroth, Alexander; Lo, Wen Ting; Müller, Rainer; Norata, Giuseppe Danilo; Falasca, Marco; Schultz, Carsten; Haucke, Volker.

In: Science, Vol. 356, No. 6341, 02.06.2017, p. 968-972.

Research output: Contribution to journalArticle

Marat, AL, Wallroth, A, Lo, WT, Müller, R, Norata, GD, Falasca, M, Schultz, C & Haucke, V 2017, 'mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate', Science, vol. 356, no. 6341, pp. 968-972. https://doi.org/10.1126/science.aaf8310
Marat AL, Wallroth A, Lo WT, Müller R, Norata GD, Falasca M et al. mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. Science. 2017 Jun 2;356(6341):968-972. https://doi.org/10.1126/science.aaf8310
Marat, Andrea L. ; Wallroth, Alexander ; Lo, Wen Ting ; Müller, Rainer ; Norata, Giuseppe Danilo ; Falasca, Marco ; Schultz, Carsten ; Haucke, Volker. / mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. In: Science. 2017 ; Vol. 356, No. 6341. pp. 968-972.
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