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

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-C2 alpha, 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-C2 alpha 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.