Akt

Akt

Akt, also known as Protein Kinase B (PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Akt is a central node in the PI3K/AKT/mTOR pathway, which is critical for cell survival and growth.

Structure

Akt is a member of the AGC kinase family, which includes Protein Kinase A (PKA), Protein Kinase G (PKG), and Protein Kinase C (PKC). The Akt protein consists of three isoforms: Akt1, Akt2, and Akt3, each encoded by a separate gene. These isoforms share a similar structure, which includes:

• A pleckstrin homology (PH) domain at the N-terminus, which binds to phosphoinositides and is crucial for membrane localization.
• A central kinase domain, which is responsible for its catalytic activity.
• A regulatory domain at the C-terminus, which is involved in the regulation of its activity.

Activation

Akt is activated through a series of phosphorylation events. The activation process involves the following steps:

1. Activation of Phosphoinositide 3-kinase (PI3K) leads to the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on the inner leaflet of the plasma membrane.
2. The PH domain of Akt binds to PIP3, recruiting Akt to the membrane.
3. Akt is phosphorylated at two key residues: threonine 308 (Thr308) in the activation loop by PDK1 (3-phosphoinositide-dependent protein kinase-1) and serine 473 (Ser473) in the hydrophobic motif by the mTORC2 complex.
4. These phosphorylation events fully activate Akt, allowing it to phosphorylate a wide range of substrates.

Function

Akt regulates a variety of cellular processes, including:

• Cell Survival and Apoptosis: Akt promotes cell survival by inhibiting apoptotic pathways. It phosphorylates and inactivates components of the apoptotic machinery, such as BAD and Caspase-9.
• Cell Growth and Proliferation: Akt stimulates cell growth and proliferation by activating mTORC1, which promotes protein synthesis and cell cycle progression.
• Metabolism: Akt plays a crucial role in glucose metabolism by facilitating the translocation of GLUT4 to the cell membrane and enhancing glycolysis.
• Angiogenesis: Akt promotes angiogenesis by upregulating the expression of VEGF (vascular endothelial growth factor).

Clinical Significance

Dysregulation of Akt signaling is implicated in various diseases, including cancer, diabetes, and cardiovascular diseases. Overactivation of Akt is commonly observed in many types of cancer, where it contributes to tumor growth and resistance to apoptosis. As a result, Akt is a target for therapeutic intervention, and several Akt inhibitors are currently being developed and tested in clinical trials.

See Also

• PI3K/AKT/mTOR pathway
• Protein Kinase A
• mTOR

References

• Manning, B. D., & Toker, A. (2017). AKT/PKB signaling: navigating the network. Cell, 169(3), 381-405.
• Vivanco, I., & Sawyers, C. L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Reviews Cancer, 2(7), 489-501.