mTORC1 (mammalian target of rapamycin complex 1), which consists of the kinase mTOR and the regulatory subunit raptor, is activated by nutrients, including amino acids. Inositol polyphosphate multikinase (IPMK), which generates the inositol polyphosphates Ins(1,4,5,6)P4 and Ins(1,3,4,5,6)P5, mediates responses to arginine in yeast, leading Kim et al. to investigate the role of IPMK in mTORC1 signaling. Compared with wild-type mouse embryo fibroblasts (MEFs), MEFs deficient in IPMK showed decreased mTORC1 signaling [as assessed by phosphorylation of the downstream substrate S6K (ribosomal protein S6 kinase)] in response to stimulation by arginine, leucine, or total amino acids, as well as attenuated increases in cell size in response to leucine. Increased phosphorylation of S6K in response to leucine did not require the catalytic activity of IPMK. Instead, IPMK appeared to stabilize the interaction of mTOR with raptor and the GTPase Rag (which mediates activation of mTORC1 by amino acids). Human IPMK interacted with mTOR in an N-terminal region encompassing amino acids 1 to 60 and with raptor through a C-terminal region. Overexpression of a fusion protein consisting of amino acids 1 to 60 of human IPMK and green fluorescent protein (GFP), followed by stimulation with leucine, reduced the amount of raptor associated with mTOR and decreased mTORC1 signaling as assessed by phosphorylation of S6K. In IPMK-depleted MEFs, reconstitution with wild-type mouse IPMK, but not with a mutant mouse form lacking the mTOR binding site, reversed deficits in mTOR-raptor interaction, mTORC1 signaling, and cell size increases seen in nonreconstituted IPMK-depleted MEFs. Thus, IPMK stabilizes the mTORC1 complex, thereby enhancing responses to amino acid stimulation.
S. Kim, S. F. Kim, D. Maag, M. J. Maxwell, A. C. Resnick, K. R. Juluri, A. Chakraborty, M. A. Koldobskiy, S. H. Cha, R. Barrow, A. M. Snowman, S. H. Snyder, Amino acid signaling to mTOR mediated by inositol polyphosphate multikinase. Cell Metab. 13, 215–221 (2011). [PubMed]