Amino acids activate mTOR complex 1 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 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 Ca(2+) ([Ca(2+)](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca(2+)](i) increases the direct binding of Ca(2+)/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.
Gulati
Pawan
P
Department of Molecular Oncogenesis, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
Gaspers
Lawrence D
LD
Dann
Stephen G
SG
Joaquin
Manel
M
Nobukuni
Takahiro
T
Natt
Francois
F
Kozma
Sara C
SC
Thomas
Andrew P
AP
Thomas
George
G
D001665:Binding Sites; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D007930:Leucine / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000378:metabolism*
D002147:Calmodulin; D033921:Vesicular Transport Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D002118:Calcium