Physiological regulation of Akt activity and stability

Area of Science:

• Cellular signaling
• Molecular biology
• Biochemistry

Background:

• Protein kinase B (Akt) is a key signaling node downstream of growth factor receptors.
• Akt regulates vital cellular processes including survival, metabolism, and proliferation.
• Dysregulated Akt activity is implicated in cancer, diabetes, and neurodegenerative diseases.

Purpose of the Study:

• To review the regulation of Akt activation and stability.
• To highlight the roles of upstream kinases, phosphatases, and protein-protein interactions.
• To discuss the implications for therapeutic interventions in Akt-altered cancers.

Main Methods:

• Literature review of published research on Akt signaling and regulation.
• Focus on phosphorylation, protein degradation, and chaperone-mediated stability.
• Analysis of the mTORC2-Akt-mTORC1 signaling loop.

Main Results:

• Akt stability is modulated by phosphorylation, including "turn motif" phosphorylation.
• Upstream kinases (e.g., mTORCs), phosphatases (PP2A, PHLPP), and inhibitors (PHLDA3) impact Akt activity.
• Ubiquitin-dependent degradation, caspase cleavage, and Hsp90 influence Akt protein levels.
• The isomerase Pin1 plays a role in Akt stability regulation.
• mTORC2 exhibits complex, sometimes contradictory, regulation of Akt phosphorylation and stability.

Conclusions:

• Understanding Akt stability regulation is critical for comprehending its role in disease.
• Targeting Akt stability pathways presents potential therapeutic strategies for human cancers.
• Further research into the intricate Akt regulatory network is warranted.