Akt Is Controlled by Bag5 through a Monoubiquitination to Polyubiquitination Switch

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The serine-threonine kinase Akt is crucial for cell survival, metabolism, proliferation, and migration.
• Tight regulation of Akt activity and stability is essential to prevent detrimental cellular conditions.
• While Akt activity regulation by phosphorylation is understood, mechanisms maintaining its stability are less clear.

Purpose of the Study:

• To investigate the role of BAG5, a chaperone regulator, in modulating Akt stability.
• To elucidate the interaction between Akt and BAG5 and its impact on Akt degradation pathways.

Main Methods:

• Characterization of BAG5 as a novel Akt interactor and substrate.
• Analysis of ubiquitination status (monoubiquitination vs. polyubiquitination) of Akt in response to BAG5.
• Assessment of Akt degradation under conditions of Hsp90 inhibition and Hsp70 overexpression with BAG5 involvement.
• Investigation of the Akt-BAG5 complex formation and dissociation dynamics in response to serum starvation and HGF stimulation.
• Evaluation of Akt activation and degradation upon BAG5 knockdown and overexpression.

Main Results:

• BAG5 acts as a novel interactor and substrate that attenuates Akt stability, working alongside Hsp70.
• BAG5 promotes the switch from monoubiquitination to polyubiquitination of Akt, enhancing its degradation.
• The Akt-BAG5 complex forms under serum-starved conditions and dissociates upon HGF stimulation, correlating with BAG5 phosphorylation.
• BAG5 knockdown reduces Akt degradation and enhances its activation, while BAG5 overexpression has the opposite effect.

Conclusions:

• Akt stability and signaling are dynamically regulated by BAG5.
• BAG5 plays a critical role in controlling Akt protein levels and activity, influenced by the availability of growth factors.