Amino acids activate mTOR Complex1 via Ca2+/CaM signaling to hVps34

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 this link is in part mediated by AA activation of mammalian Target Of Rapamycin (mTOR) Complex1. AAs appear to mediate this response through class 3 PI3K, or hVps34, rather than through the canonical class 1 PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca 2+ ([Ca 2+ ]i), which triggers mTOR Complex1 and hVps34 activation. We demonstrate that the rise in [Ca 2+ ]i increases the direct binding of Ca 2+ /CaM to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.