Amino Acids Activate mTOR Complex 1 via Ca2+/CaM Signaling to hVps34

Pawan Gulati, Lawrence D. Gaspers, Stephen G. Dann, Manel Joaquin, Takahiro Nobukuni, Francois Natt, Sara C. Kozma, Andrew P. Thomas, George Thomas

研究成果: Article査読

288 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)456-465
ページ数10
ジャーナルCell Metabolism
7
5
DOI
出版ステータスPublished - 2008 5 7
外部発表はい

ASJC Scopus subject areas

  • 生理学
  • 分子生物学
  • 細胞生物学

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