Amino Acid Signaling to mTOR Mediated by Inositol Polyphosphate Multikinase

The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell metabolism (Impact Factor: 17.57). 02/2011; 13(2):215-21. DOI: 10.1016/j.cmet.2011.01.007
Source: PubMed


mTOR 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.

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    • "Our data showing reduced expression levels of IPMK in HFD mice indicate that this important component of nutrient sensing (Hardie et al., 2012) may play a mechanistic role in regulating the insulin–PI3K–Akt–mTOR pathway in the telencephalon. We previously reported that IPMK, which possesses both inositol phosphate kinase and lipid kinase activities , regulates amino acid signaling to mTORC1 (Kim et al., 2011). This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mTOR and raptor, which maintains the mTOR–raptor association. "
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    • "Growth factor regulated pathways leading to the activation of mTORC1 via AKT have been extensively characterized, while the mechanisms by which nutrients are able to activate mTORC1 remains ill-defined.57 Earlier studies have demonstrated that amino acid-dependent activation of mTORC1 requires the Rag guanosine triphosphate (GTP) ases,58,59 while additional studies have implicated other proteins, including MAP4K3 (mitogen-activated protein kinase kinase kinase kinase),60 and inositol polyphosphate monokinase (IMPK);61 however, how these molecules interact to mediate nutrient signaling requires further investigation. The class III PI3-K hVps34 has also been implicated in nutrient signaling to mTORC1; this regulation is dependent on the associated kinase hVps15 and independent of TSC (tuberous sclerosis complex).54,55 "
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    • "In IPMK knockout embryonic stem (ES) cells [27], we observed a significant decrease in Akt activation upon Salmonella infection, compared to wild type control cells (Figure 5B and C). We also examined mouse embryonic fibroblast cells (MEFs) lacking IPMK [35]. In contrast to ES cells, we did not see a decrease in Akt activation in IPMK-/- MEFs when infected with wild type Salmonella compared to WT MEFs (Figure S4). "
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