Proteomics

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PIP4kγ is a substrate for mTORC1


ABSTRACT: Phosphatidylinositol-5-phosphate 4-kinases (PIP4ks) are a family of lipid kinases that specifically use PI-5-P as a substrate to synthesize 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 an unphosphorylated wild-type PIP4kγ and 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.

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cell Culture

SUBMITTER: Deborah Sarkes  

LAB HEAD: Lucia E. Rameh

PROVIDER: PXD001340 | Pride | 2016-05-04

REPOSITORIES: Pride

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Publications

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

Mackey Ashley M AM   Sarkes Deborah A DA   Bettencourt Ian I   Asara John M JM   Rameh Lucia E LE  

Science signaling 20141104 350


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  ...[more]

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