PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation.

Mackey AM, Sarkes DA, Bettencourt I, Asara JM, Rameh LE
Sci Signal. 2014 7 (350): ra104

PMID: 25372051 · PMCID: PMC4579097 · DOI:10.1126/scisignal.2005191

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 γ isoform of PIP4k stimulated signaling through mammalian TORC1 (mTORC1). Knockdown of PIP4kγ 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. PIP4kγ knockdown inhibited the nutrient-independent activation of mTORC1 in Tsc2 knockdown cells and reduced basal mTORC1 signaling in wild-type cells. PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ 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 PIP4kγ or a phosphorylation-defective mutant and decreased by overexpression of a phosphorylation-mimetic mutant. Together, these results demonstrate that PIP4kγ and mTORC1 interact in a self-regulated feedback loop to maintain low and tightly regulated mTORC1 activation during starvation.

Copyright © 2014, American Association for the Advancement of Science.

MeSH Terms (16)

Animals Cytoplasm Fibroblasts HEK293 Cells HeLa Cells Humans Mechanistic Target of Rapamycin Complex 1 Mice Multiprotein Complexes Mutation Phosphorylation Phosphotransferases (Alcohol Group Acceptor) Signal Transduction TOR Serine-Threonine Kinases Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins

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