Phosphatidylinositol 3,5-bisphosphate plays a role in the activation and subcellular localization of mechanistic target of rapamycin 1

• Published in: Molecular biology of the cell 2012-08, Vol.23 (15), p.2955-2962
• Main Authors: Bridges, Dave, Ma, Jing-Tyan, Park, Sujin, Inoki, Ken, Weisman, Lois S, Saltiel, Alan R
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adaptor Proteins, Signal Transducing - metabolism; Adipocytes - cytology; Adipocytes - metabolism; Animals; Cell Membrane - metabolism; Class III Phosphatidylinositol 3-Kinases - metabolism; HEK293 Cells; Humans; Insulin - metabolism; Lipid Metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - metabolism; Proteins - metabolism; Regulatory-Associated Protein of mTOR; Signal Transduction; TOR Serine-Threonine Kinases
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E11-12-1034

The kinase complex mechanistic target of rapamycin 1 (mTORC1) plays an important role in controlling growth and metabolism. We report here that the stepwise formation of phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)) regulates the cell type-specific activation and localization of mTORC1. PI(3)P formation depends on the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2α, as well as the class III PI3K Vps34, while PI(3,5)P(2) requires the phosphatidylinositol-3-phosphate-5-kinase PIKFYVE. In this paper, we show that PIKFYVE and PI3K-C2α are necessary for activation of mTORC1 and its translocation to the plasma membrane in 3T3-L1 adipocytes. Furthermore, the mTORC1 component Raptor directly interacts with PI(3,5)P(2). Together these results suggest that PI(3,5)P(2) is an essential mTORC1 regulator that defines the localization of the complex.