AKT1 - RAC-alpha serine/threonine-protein kinase 1 | Elisa - Clia - Antibody - Protein

Background:

The AKT (also known as Protein Kinase B) is a pivotal enzyme involved in regulating various cellular processes like metabolism, proliferation, survival, and growth. It acts downstream of phosphoinositide 3-kinase (PI3K) signaling pathway, which is activated by growth factors and cytokines. RAC-alpha serine/threonine-protein kinase is the full name of AKT. It belongs to the AGC (protein kinase A/protein kinase G/protein kinase C) family of kinases. AKT has three isoforms: AKT1, AKT2, and AKT3. Each isoform has slightly different tissue distributions and roles but shares the same basic structure and mechanism of action.Activation of AKT typically occurs through phosphorylation at two key residues: threonine 308 (Thr308) and serine 473 (Ser473). Once activated, AKT phosphorylates various downstream targets, including transcription factors, metabolic enzymes, and cell cycle regulators, ultimately leading to diverse cellular responses. Dysregulation of AKT signaling is implicated in various diseases, including cancer, diabetes, and cardiovascular diseases. Therefore, AKT has emerged as a significant target for therapeutic interventions in these conditions.

Protein Structure:

• Domains:
• Pleckstrin Homology (PH) Domain: This domain binds phosphoinositides, specifically PIP3 (phosphatidylinositol-3,4,5-trisphosphate), recruiting AKT1 to the plasma membrane.
• Catalytic Kinase Domain: The central kinase domain is responsible for the enzyme's catalytic activity, transferring phosphate groups to substrate proteins.
• Regulatory Domain: The C-terminal regulatory domain contains a hydrophobic motif crucial for full activation.
• Activation: Full activation of AKT1 requires two phosphorylation events:
• Thr308: Located in the activation loop, phosphorylated by PDK1 (phosphoinositide-dependent kinase-1).
• Ser473: Located in the hydrophobic motif, phosphorylated by mTORC2 (mechanistic target of rapamycin complex 2).

Classification and Subtypes:

• Family: AKT belongs to the AGC (PKA/PKG/PKC) kinase superfamily.
• Isoforms: AKT1 (PKBα), AKT2 (PKBβ), and AKT3 (PKBγ) are the three isoforms, each encoded by separate genes and with distinct tissue distributions and functions.

Function and Biological Significance:

• Cell Survival and Apoptosis: AKT1 promotes cell survival by inhibiting pro-apoptotic proteins such as BAD and caspase-9 and activating anti-apoptotic pathways.
• Cell Growth and Proliferation: It stimulates protein synthesis and cell growth by activating mTOR (mechanistic target of rapamycin) and other downstream targets.
• Glucose Metabolism: AKT1 enhances glucose uptake and glycogen synthesis by modulating the activity of glucose transporters and glycogen synthase kinase-3 (GSK-3).
• Angiogenesis: AKT1 promotes angiogenesis by upregulating VEGF (vascular endothelial growth factor) expression.
• Migration and Invasion: AKT1 regulates cell migration and invasion through the modulation of cytoskeletal dynamics and matrix metalloproteinases.

Interactions:

• Upstream Regulators: Phosphoinositide 3-kinase (PI3K) is a primary upstream activator of AKT1, producing PIP3, which recruits AKT1 to the membrane.
• Substrates: AKT1 phosphorylates a variety of substrates, including GSK-3, FOXO transcription factors, mTOR, BAD, and caspase-9.
• Complex Formation: AKT1 forms complexes with several proteins, including PDK1, mTORC2, and heat shock proteins, which are essential for its activation and function.

Clinical Issues:

• Cancer: AKT1 is frequently hyperactivated in various cancers due to mutations, amplifications, or upstream pathway alterations (e.g., PI3K mutations, PTEN loss). It contributes to tumor growth, survival, and resistance to therapy.
• Diabetes and Metabolic Disorders: Dysregulation of AKT1 signaling is implicated in insulin resistance and type 2 diabetes due to its central role in glucose metabolism.
• Cardiovascular Diseases: AKT1 plays a role in cardiovascular health by regulating endothelial cell function and cardiomyocyte survival, and its dysregulation is linked to atherosclerosis and heart failure.
• Neurological Disorders: AKT1 signaling is involved in brain development and neuronal survival. Abnormal AKT1 activity is associated with neurodegenerative diseases and psychiatric disorders.

Summary:

AKT1 is a serine/threonine kinase pivotal in regulating diverse cellular processes, including cell survival, growth, metabolism, and migration. Activated by PI3K-generated phosphoinositides, AKT1 undergoes phosphorylation at key residues for full activation. Dysregulation of AKT1 is implicated in various diseases, particularly cancer, due to its role in promoting cell survival and growth. Understanding AKT1 signaling pathways offers potential therapeutic targets for treating cancer, metabolic disorders, cardiovascular diseases, and neurological conditions.