| First Author | Mackey AM | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 350 | Pages | ra104 |
| PubMed ID | 25372051 | Mgi Jnum | J:259834 |
| Mgi Id | MGI:6143879 | Doi | 10.1126/scisignal.2005191 |
| Citation | Mackey AM, et al. (2014) PIP4kgamma is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation. Sci Signal 7(350):ra104 |
| abstractText | Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases that specifically use phosphatidylinositol 5-monophosphate (PI-5-P) as a substrate to synthesize phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Suppression of PIP4k function in Drosophila results in smaller cells and reduced target of rapamycin complex 1 (TORC1) signaling. We showed that the gamma isoform of PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kgamma reduced cell mass in cells in which mTORC1 is constitutively activated by Tsc2 deficiency. In Tsc2 null cells, mTORC1 activation was partially independent of amino acids or glucose and glutamine. PIP4kgamma knockdown inhibited the nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced basal mTORC1 signaling in wild-type cells. PIP4kgamma was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kgamma was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi. Furthermore, basal mTORC1 signaling was enhanced by overexpression of unphosphorylated wild-type PIP4kgamma or a phosphorylation-defective mutant and decreased by overexpression of a phosphorylation-mimetic mutant. Together, these results demonstrate that PIP4kgamma and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly regulated mTORC1 activation during starvation. |
