Regulation of the mammalian target of rapamycin complex 2 (mTORC2)

The growth controlling mammalian Target of Rapamycin (mTOR) is a conserved
Ser/Thr kinase found in two structurally and functionally distinct complexes, mTORC1
and mTORC2. The tumor suppressor TSC1-TSC2 complex inhibits mTORC1 by
acting on the small GTPase Rheb, but the role of TSC1-TSC2 and Rheb in the
regulation of mTORC2 is unclear. Here we examined the role of TSC1-TSC2 in the
regulation of mTORC2 in human embryonic kidney 293 cells. Induced knockdown of
TSC1 and TSC2 (TSC1/2) stimulated mTORC2-dependent actin cytoskeleton
organization and Paxillin phosphorylation. Furthermore, TSC1/2 siRNA increased
mTORC2-dependent Ser473 phosphorylation of plasma membrane bound,
myristoylated Akt/PKB. This suggests that loss of Akt/PKB Ser473 phosphorylation
in TSC mutant cells, as reported previously, is due to inhibition of Akt/PKB
localization rather than inhibition of mTORC2 activity. Amino acids and
overexpression of Rheb failed to stimulate mTORC2 signaling. Thus, TSC1-TSC2
also inhibits mTORC2, but possibly independently of Rheb. Our results suggest that
mTORC2 hyperactivation may contribute to the pathophysiology of diseases such as
cancer and Tuberous Sclerosis Complex.