Akt/PKB signaling pathway

Akt/PKB signaling pathway, also known as the PI3K/Akt pathway, is a critical cell signaling pathway that plays a significant role in regulating various cellular processes including metabolism, proliferation, cell survival, growth, and angiogenesis. This pathway is activated by various types of cellular stimuli, including growth factors, insulin, and other extracellular signals, leading to a wide range of physiological responses.

Overview

The Akt/PKB signaling pathway is initiated when growth factors or other signaling molecules bind to their respective receptor tyrosine kinases (RTKs) on the cell surface. This binding triggers the activation of phosphoinositide 3-kinase (PI3K), which then converts phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3). The increase in PIP3 levels on the plasma membrane serves as a docking site for Akt (also known as Protein Kinase B or PKB) and its upstream activator, phosphoinositide-dependent kinase-1 (PDK1). Akt is then phosphorylated and activated by PDK1 and possibly other kinases such as the mammalian target of rapamycin complex 2 (mTORC2).

Once activated, Akt phosphorylates a variety of downstream targets involved in the regulation of cell survival, growth, proliferation, glucose metabolism, and angiogenesis. This includes the inactivation of pro-apoptotic factors and the activation of survival genes. The pathway is negatively regulated by the phosphatase and tensin homolog (PTEN) which dephosphorylates PIP3 back to PIP2, thus inhibiting Akt activation.

Key Components

• Phosphoinositide 3-kinase (PI3K): Converts PIP2 to PIP3, initiating the pathway.
• Akt (Protein Kinase B, PKB): A serine/threonine-specific protein kinase that is the central node of the pathway.
• Phosphoinositide-dependent kinase-1 (PDK1): Activates Akt by phosphorylation.
• mTORC2 (mammalian target of rapamycin complex 2): May also phosphorylate and activate Akt.
• PTEN (phosphatase and tensin homolog): Negatively regulates the pathway by converting PIP3 back to PIP2.

Physiological Functions

The Akt/PKB signaling pathway is involved in a myriad of cellular functions. It promotes glucose uptake and glycogen synthesis by modulating the activity of various enzymes and transporters. In terms of cell survival, Akt inhibits apoptosis by phosphorylating and inactivating components of the apoptotic machinery. It also stimulates cell growth and proliferation by modulating the activity of proteins involved in the cell cycle.

Pathological Implications

Dysregulation of the Akt/PKB signaling pathway has been implicated in various diseases, particularly in cancer. Overactivation of this pathway can lead to uncontrolled cell growth and survival, contributing to tumor development and progression. Additionally, mutations in components of the pathway, such as PI3K or PTEN, are common in many types of cancer. The pathway is also involved in diabetes mellitus, as it plays a crucial role in insulin signaling and glucose homeostasis.

Conclusion

The Akt/PKB signaling pathway is a fundamental pathway in cells, controlling a wide range of physiological processes. Its importance is underscored by its involvement in many diseases, making it a target for therapeutic intervention in conditions like cancer and diabetes.