Differential involvement of IκB kinases a and β in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors such as insulin, cytokines such as TNF, and Akt-dependent signaling associated with oncoprotein expression. mTOR is negatively controlled by the tuberous sclerosis complex 1/2 (TSC1/2), and activation of Akt induces phosphorylation of TSC2, which blocks the repressive TSC1/2 activity. Previously, we showed that activation of mTOR in PTEN-deficient cancer cells involves licB kinase (IKK) a, a catalytic subunit of the IKK complex that controls NF-kappa B activation. Recently, a distinct IKK subunit, IKK beta, was shown to phosphorylate TSC1 to promote mTOR activation in an Akt-independent manner in certain cells stimulated with TNF and in some cancer cells. In this study, we have explored the involvement of both IKK alpha and IKK beta in insulin- and TNF-induced mTOR activation. Insulin activation of mTOR requires Akt in a manner that involves IKKa, preferentially to IKK beta, and TSC2 phosphorylation. TNF, in most cells examined, activates Akt to use IKK alpha to control mTOR activation. In MCF7 cells, TNF does not activate Akt and requires IKK beta to activate mTOR. The results show that Akt-dependent signaling, induced by cytokines or insulin, alters the IKK subunit-dependent control of mTOR.