PI3K/Akt promotes feedforward mTORC2 activation through IKKα

Area of Science:

• Molecular Biology
• Cancer Biology
• Cell Signaling

Background:

• Akt is crucial for cell survival, growth, and metabolism, and its dysregulation is common in cancers.
• Akt activity is regulated by phosphorylation at Thr308 (by PDK1) and Ser473 (by mTORC2 complex).
• Inhibitor of nuclear factor kappa-B kinase-alpha (IKKα) is known to regulate mTORC1, but its role in Akt activation was unexplored.

Purpose of the Study:

• To investigate the potential involvement of IKKα in controlling Akt activity.
• To determine if IKKα's role in Akt activation involves the mTORC2 complex.

Main Methods:

• Co-immunoprecipitation assays to assess IKKα and mTORC2 association.
• Western blotting to analyze phosphorylation levels of Akt and downstream targets.
• Experiments involving IKKα knockdown to evaluate its effect on Akt activation.

Main Results:

• IKKα associates with mTORC2 in cancer cells, dependent on PI3K/Akt activity.
• IKKα positively regulates Akt phosphorylation at both Ser473 and Thr308.
• IKKα enhances mTORC2 kinase activity towards Akt, promoting phosphorylation of FOXO3a and GSK3β.

Conclusions:

• IKKα acts as a feedforward regulator of mTORC2 and Akt activation.
• IKKα enhances mTORC2 activity, leading to increased Akt phosphorylation and downstream signaling.
• IKKα represents a potential therapeutic target for blocking mTORC2 and Akt activation in certain cancers.