mTOR and Akt Signaling in Cancer: SGK Cycles In Alex Toker  Molecular Cell  Volume 31, Issue 1, Pages 6-8 (July 2008) DOI: 10.1016/j.molcel.2008.06.007 Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 1 mTOR Signaling to Akt and SGK Converge to Regulate p27 Localization Growth factors stimulate PI3K activation, which recruits PDK-1 to the membrane, leading to phosphorylation of Akt at the T-loop residue T308. PDK-1 also phosphorylates SGK at T256 in intracellular locations. Akt then phosphorylates TSC2 inhibiting its RheB GAP activity, stimulating GTP loading of RheB, which in turn potently activates mTOR in the mTORC1 complex. The rapamycin-insensitive mTORC2 complex directly phosphorylates Akt at the hydrophobic motif S473, leading to full Akt activation. The TSC complex is also required for efficient activation of TORC2. Whereas mTORC2 is required for Akt activation, mTORC1 directly phosphorylates SGK at the hydrophobic motif S422, leading to activation. Both Akt and SGK can directly phosphorylate p27 at T157, leading to impaired nuclear import and cytoplasmic retention. The AMPK pathway signals to the TSC complex and promotes mTOR activation in response to nutrients such as glucose and amino acids. The net effect is inhibition of cell-cycle progression leading to growth arrest. (Green arrows denote direct phosphorylation reactions). Molecular Cell 2008 31, 6-8DOI: (10.1016/j.molcel.2008.06.007) Copyright © 2008 Elsevier Inc. Terms and Conditions