AKT3 - RAC-gamma serine/threonine-protein kinase 3 | Elisa - Clia - Antibody - Protein

Background:

AKT3, also known as RAC-gamma serine/threonine-protein kinase, is one of the three isoforms of the AKT (Protein Kinase B) family of serine/threonine kinases. Like AKT1 and AKT2, AKT3 plays a crucial role in regulating various cellular processes, including cell survival, proliferation, growth, and metabolism. AKT3 is activated downstream of the phosphoinositide 3-kinase (PI3K) signaling pathway, which is activated by growth factors and other extracellular stimuli. Activation of AKT3 occurs through phosphorylation at key residues, including threonine 305 (Thr305) and serine 472 (Ser472). Once activated, AKT3 phosphorylates a wide range of substrates involved in diverse cellular functions. While AKT1 and AKT2 are ubiquitously expressed in many tissues, AKT3 exhibits a more restricted pattern of expression, with higher expression levels observed in the brain, heart, and skeletal muscle. This tissue-specific expression pattern suggests distinct roles for AKT3 in these tissues. AKT3 is involved in brain development and neuronal survival. Studies have shown that AKT3 plays a critical role in regulating neuronal migration, axon outgrowth, and dendritic arborization during brain development. Dysregulation of AKT3 signaling has been implicated in various neurological disorders, including autism spectrum disorders and epilepsy. AKT3 is also involved in other cellular processes such as cell proliferation, survival, and metabolism. Dysregulation of AKT3 signaling has been implicated in various diseases, including cancer, metabolic disorders, and cardiovascular diseases.

Protein Structure:

• N-Terminal Pleckstrin Homology (PH) Domain: Binds to phosphoinositides, specifically PIP3, which recruits AKT3 to the plasma membrane where it can be activated.
• Central Kinase Domain: This domain is responsible for the enzyme's catalytic activity, phosphorylating various substrate proteins on serine and threonine residues.
• C-Terminal Regulatory Domain: Contains a hydrophobic motif crucial for the full activation of the kinase, including phosphorylation sites that regulate its activity.

Classification and Subtypes:

• Family: AKT3 is part of the AGC kinase family, a group of kinases that include protein kinase A, G, and C.
• Subtypes: AKT3 does not have subtypes, but it is one of the three isoforms of AKT kinases, each with distinct as well as overlapping functions.

Function and Biological Significance:

• Brain Development: AKT3 plays a vital role in brain development and function, with high expression in the brain and central nervous system. It is involved in neural growth and survival.
• Cell Survival and Growth: Like other AKT isoforms, AKT3 promotes cell survival and growth by phosphorylating and inhibiting pro-apoptotic factors such as BAD and GSK-3β, and by activating mTORC1.
• Angiogenesis: AKT3 is involved in promoting angiogenesis, the formation of new blood vessels, which is important in both normal physiological processes and in cancer.
• Cell Proliferation and Size: AKT3 is important for cell proliferation and size, particularly in neurons, contributing to the proper functioning of the brain.

Interactions:

• Upstream Regulators: AKT3 is activated by PI3K through the production of PIP3, which recruits AKT3 to the membrane where it is phosphorylated and activated by PDK1 and mTORC2.
• Downstream Targets: AKT3 phosphorylates numerous substrates including GSK-3β, FOXO transcription factors, mTOR, and AS160, influencing various cellular processes.
• Scaffold Proteins: AKT3 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 AKT3 is linked to several types of cancer, including breast, prostate, and glioblastoma. It promotes tumor cell survival, growth, and resistance to therapies.
• Neurological Disorders: Dysregulation of AKT3 has been implicated in neurological disorders, given its role in brain development and function. Mutations or altered expression can affect neuronal growth and survival.
• Rare Genetic Disorders: Mutations in AKT3 can lead to conditions such as macrocephaly and epilepsy, highlighting its importance in brain size regulation and neuronal function.

Summary:

AKT3 is a crucial member of the AKT kinase family, with specific roles in brain development, cell survival, and growth. Its activation and functions are essential for normal cellular processes and brain function. Dysregulation of AKT3 is associated with various pathologies, including cancers and neurological disorders, making it an important target for therapeutic interventions. Understanding the specific roles and regulatory mechanisms of AKT3 provides valuable insights into its contribution to health and disease.