Protein kinase B

Protein Kinase B

Diagram of signal transduction pathways including Protein Kinase B

Protein Kinase B (PKB), also known as Akt, 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. PKB is a central node in the PI3K/AKT/mTOR pathway, which is critical for cell survival and growth.

Structure

Protein Kinase B is composed of three isoforms: Akt1, Akt2, and Akt3, each encoded by separate genes. These isoforms share a similar structure, consisting of an N-terminal pleckstrin homology (PH) domain, a central kinase domain, and a C-terminal regulatory domain. The PH domain is responsible for binding to phosphoinositides, which localizes PKB to the plasma membrane where it is activated.

Activation

PKB is activated through a series of phosphorylation events. The activation process begins with the binding of growth factors to receptor tyrosine kinases, leading to the activation of phosphoinositide 3-kinase (PI3K). PI3K catalyzes the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits PKB to the membrane via its PH domain. Once at the membrane, PKB is phosphorylated at two key residues: Thr308 in the activation loop and Ser473 in the hydrophobic motif, by PDK1 and mTORC2, respectively.

Function

PKB regulates a variety of cellular processes:

• Glucose Metabolism: PKB promotes glucose uptake by facilitating the translocation of GLUT4 to the cell membrane and enhances glycolysis by phosphorylating and activating key enzymes.
• Cell Survival: PKB inhibits apoptosis by phosphorylating and inactivating components of the apoptotic machinery, such as BAD and caspase-9.
• Cell Growth and Proliferation: PKB stimulates cell growth by activating the mTOR pathway and promotes cell cycle progression by phosphorylating and inhibiting cell cycle inhibitors like p21 and p27.

Clinical Significance

Dysregulation of PKB signaling is implicated in various diseases, including cancer, diabetes, and cardiovascular diseases. Overactivation of PKB is commonly observed in cancers, where it contributes to tumor growth and resistance to apoptosis. Inhibitors targeting the PI3K/AKT/mTOR pathway are being developed as potential therapeutic agents for cancer treatment.

Related Pages

• Signal transduction
• Phosphoinositide 3-kinase
• mTOR
• Apoptosis
• Cancer