AKT2 - RAC-beta serine/threonine-protein kinase 2 | Elisa - Clia - Antibody - Protein

Background:

AKT2, also known as RAC-beta serine/threonine-protein kinase, is one of the three isoforms of the AKT (Protein Kinase B) family of serine/threonine kinases. Like other AKT isoforms, AKT2 plays a crucial role in various cellular processes, including metabolism, cell survival, proliferation, and growth. AKT2 is a downstream effector of the PI3K (phosphoinositide 3-kinase) signaling pathway. Activation of AKT2 occurs through phosphorylation at key residues, including threonine 309 (Thr309) and serine 474 (Ser474). Once activated, AKT2 phosphorylates a wide range of substrates involved in diverse cellular functions. AKT2 regulates glucose uptake by promoting the translocation of glucose transporter type 4 (GLUT4) to the cell membrane, thereby facilitating glucose uptake into cells, particularly in insulin-responsive tissues like muscle and adipose tissue. Dysregulation of AKT2 signaling has been implicated in insulin resistance and type 2 diabetes. AKT2 is also involved in other cellular processes such as cell proliferation, survival, and migration. Dysregulation of AKT2 signaling has been implicated in various diseases, including cancer, metabolic disorders, and cardiovascular diseases.

Protein Structure:

• N-Terminal Pleckstrin Homology (PH) Domain: This domain allows AKT2 to bind to phosphoinositides, specifically PIP3, which recruits it to the plasma membrane where it becomes activated.
• Central Kinase Domain: The core domain responsible for its catalytic activity, phosphorylating various substrate proteins on serine and threonine residues.
• C-Terminal Regulatory Domain: Contains a hydrophobic motif crucial for full activation of the kinase.

Classification and Subtypes:Classification and Subtypes:

• Family: AKT2 is part of the AGC (protein kinase A, G, and C) kinase family, which includes other isoforms such as AKT1 and AKT3.
• Subtypes: AKT2 does not have subtypes, but its functions and regulatory mechanisms are distinct from AKT1 and AKT3, despite their structural similarities.

Function and Biological Significance:

• Glucose Metabolism: AKT2 plays a vital role in mediating insulin's effects on glucose uptake, particularly in muscle and adipose tissues. It promotes the translocation of GLUT4 glucose transporters to the cell membrane.
• Cell Survival and Growth: AKT2 promotes cell survival and growth by phosphorylating and inhibiting pro-apoptotic factors such as BAD and GSK-3β, and by activating mTORC1.
• Lipid Metabolism: AKT2 is involved in lipogenesis and inhibits lipolysis, contributing to fat storage in adipocytes.
• Cell Migration and Invasion: AKT2 influences cell migration and invasion, which is important in cancer metastasis.

Interactions:

• Upstream Regulators: AKT2 is activated by PI3K through the production of PIP3, which recruits AKT2 to the membrane where it is phosphorylated and activated by PDK1 and mTORC2.
• Downstream Targets: AKT2 phosphorylates numerous substrates including GSK-3β, FOXO transcription factors, mTOR, and AS160, affecting various cellular processes.
• Scaffold Proteins: AKT2 interacts with scaffold proteins such as IRS-1 and 14-3-3 proteins, which aid in its localization and function.

Clinical Issues:

• Cancer: Overexpression or hyperactivation of AKT2 is linked to the development and progression of various cancers, including pancreatic, ovarian, and breast cancers. It promotes cancer cell survival, growth, and metastasis.
• Diabetes and Insulin Resistance: Mutations or dysregulation of AKT2 are associated with severe insulin resistance and type 2 diabetes, as AKT2 is crucial for insulin-mediated glucose uptake.
• Rare Genetic Disorders: Mutations in AKT2 can lead to conditions such as familial partial lipodystrophy and severe insulin resistance.

Summary:

AKT2 is a critical kinase in the AKT family, predominantly involved in regulating glucose metabolism and insulin signaling. Its activation and functions are crucial for normal cellular metabolism, growth, and survival. Dysregulation of AKT2 is implicated in various pathologies, including cancer and metabolic disorders, making it a significant target for therapeutic interventions. Understanding the specific roles and regulatory mechanisms of AKT2 provides valuable insights into its contribution to health and disease.