Amino Acid Signaling to mTOR Mediated by Inositol Polyphosphate Multikinase

SummarymTOR complex 1 (mTORC1; mammalian target of rapamycin [mTOR] in complex with raptor) is a key regulator of protein synthesis and cell growth in response to nutrient amino acids. Here we report that inositol polyphosphate multikinase (IPMK), which possesses both inositol phosphate kinase and lipid kinase activities, regulates amino acid signaling to mTORC1. This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mTOR and raptor, which maintains the mTOR-raptor association. Thus, IPMK appears to be a physiologic mTOR cofactor, serving as a determinant of mTORC1 stability and amino acid-induced mTOR signaling. Substances that block IPMK-mTORC1 binding may afford therapeutic benefit in nutrient amino acid-regulated conditions such as obesity and diabetes.

► IPMK is involved in mTOR-raptor binding and amino acid-induced mTORC1 signaling ► IPMK is an mTOR cofactor ► IPMK mediates amino acid signaling by stabilizing mTOR-raptor interaction ► Regulation of mTOR by IPMK depends on the mammal-specific amino terminus of IPMK