Abstract
The ser-thr Akt plays a critical role in the regulation of cell survival, cell growth and proliferation, as well as energy metabolism and is dysregulated in many cancers. The regulation of Akt activity depends on the phosphorylation at two sites: (i) Thr308 in the activation loop by phosphoinositide-dependent kinase-1 (PDK1) and (ii) Ser473 hydrophobic motif at the carboxyl terminus by a second activity termed PDK2, which is the mTORC2 complex composed of mTOR, rictor, and Sin1. Previously we demonstrated that IKKα, a component of the IKK complex that controls NF-κB activation, participates in the Akt-dependent regulation of mTORC1. Here we have explored a potential involvement of IKKα in controlling Akt activity and whether this may involve mTORC2. The experiments show that IKKα associates with mTORC2 in several cancer cells in a manner dependent on PI3K/Akt activity and that IKKα positively promotes Akt phosphorylation at Ser473 and at Thr308. Moreover, IKKα enhances mTORC2 kinase activity directed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3β, but not other Akt-associated targets such as TSC2 and PRAS40, indicating the existence of multiple mechanisms of Akt activation in cells. In addition, loss of IKKα suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKKα serves as a feedforward regulator of mTORC2 and that IKKα could serve as a key therapeutic target to block mTORC2 and Akt activation in some cancers.
Highlights
Akt family proteins are an evolutionarily conserved group of serine-threonine kinases which phosphorylate key substrate involved in numerous cellular pathways [1, 2]
The results revealed that knockdown of IKKα suppressed phosphorylation of Akt at both ser473 and thr308 (Figure 1A), which are important phosphorylation residues required for full Akt activation
Identical results were obtained using distinct IKKα siRNA pools (Figure 1B). These results indicate that IKKα plays an important role in the activation of both Akt and mTORC1 independent of PTEN loss
Summary
Akt family proteins are an evolutionarily conserved group of serine-threonine kinases which phosphorylate key substrate involved in numerous cellular pathways [1, 2]. MTORC1 can be activated downstream of signaling induced by growth factors, such as IGF-1 and insulin, in a manner controlled downstream of PI3K/Akt [7, 8]. It has been shown that active Akt activates mTORC1 through phosphorylation of the tumor suppressor TSC2 to release TSC2 inhibition of the GTPase Rheb leading to positive regulation of mTORC1 [7 - 11]. MTORC2, which contains mTOR, Rictor, Sin and GβL, is rapamycin-insensitive and has been reported to regulate the actin cytoskeleton by modulating protein kinase C and Rho-family small GTPases [2, 4, 8]. Mechanisms for inducible control of mTORC2 activity have been elusive, but it was shown recently that PIP3, generated downstream of PI3K, binds to Sin to promote mTORC2 activity [14]. A separate study indicated that Sin acetylation is important for mTORC2 activation [15]
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