Journal
CELL METABOLISM
Volume 7, Issue 5, Pages 456-465Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2008.03.002
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Funding
- NCI NIH HHS [U01 CA084292, CA84292-06] Funding Source: Medline
- NIDDK NIH HHS [DK73802, R01 DK073802-03, R01 DK078019, R01 DK073802, DK38422] Funding Source: Medline
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Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca2+ ([Ca2+](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca2+](i) increases the direct binding of Ca2+/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.
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