Akt Isoforms: Distinct Functions in Health and Disease

The enzyme Akt, also called Protein Kinase B (PKB), is a protein that serves as a central hub in cellular communication, governing activities like cell growth, proliferation, and survival. Different versions of this protein, known as isoforms, are products of distinct genes. While structurally similar, these isoforms are tailored for specific tasks in different tissues, allowing for precise cellular regulation.

The Akt Signaling Pathway

Akt primarily exerts its influence through the PI3K/Akt signaling pathway, which converts external cues like growth factors or insulin into specific cellular actions. The process begins when these molecules bind to receptors on the cell surface. This binding triggers a cascade of internal events that activates the enzyme phosphoinositide 3-kinase (PI3K).

Once activated, PI3K generates a lipid molecule in the cell membrane that acts as a docking site for Akt. This recruitment to the membrane allows other proteins to modify and activate Akt. Akt then phosphorylates a wide array of downstream targets, which carries out the instructions from the initial external signal.

Akt activation promotes cell survival by interfering with apoptosis, or programmed cell death. It also encourages cells to enter the cell cycle, driving proliferation and tissue growth. The pathway plays a part in cellular metabolism by helping manage the uptake and use of nutrients.

Defining the Akt Isoforms

The Akt protein family has three main isoforms: Akt1, Akt2, and Akt3. Encoded by separate genes, they share up to 80% structural similarity, but their expression patterns and functional roles are distinct. This distribution throughout the body hints at their specialized tasks.

Akt1 is expressed in nearly all cell types, suggesting its involvement in processes common to most tissues. In contrast, Akt2 expression is concentrated in insulin-responsive tissues like skeletal muscle, fat cells (adipocytes), and the liver. This points toward its specialized role in metabolic regulation.

Akt3 has a more restricted expression pattern, found predominantly in the brain and testes, implying a function within the central nervous system. Although all three isoforms share basic structural domains, subtle differences in their regulatory regions are thought to cause their unique substrate preferences and distinct biological functions.

Distinct Biological Functions

Akt1’s primary role is mediating cell growth and survival. Studies involving the deletion of the Akt1 gene in mice confirm its importance in development, as these animals exhibit growth retardation and reduced organ size. This isoform promotes tissue growth by ensuring cells proliferate when needed and are protected from premature death.

Akt2 is the isoform that governs metabolic processes, particularly glucose homeostasis. As the main player in the insulin signaling pathway, Akt2 activation prompts cells to take up glucose from the bloodstream. When insulin binds to a receptor, Akt2 drives the movement of glucose transporters to the cell surface, allowing sugar to enter the cell. The absence of Akt2 leads to impaired glucose uptake and insulin resistance.

Akt3’s specialized role centers on the development and health of the central nervous system, where it regulates brain size and neuron health. Research connects Akt3 activity to the growth of neurons and the overall size of the brain. It fine-tunes pathways for neuronal survival and function, contributing to the brain’s architecture.

Implications in Human Disease

Dysregulation of the Akt isoforms is linked to different human diseases. Because of its growth-promoting nature, Akt1 over-activation is a common feature in many cancers. Excessive Akt1 signaling leads to the uncontrolled cell proliferation and suppression of cell death that characterize tumor growth, making it a therapeutic target.

Impairments in Akt2 signaling are connected to metabolic disorders like type 2 diabetes. Insulin resistance in this condition is often linked to faulty Akt2 activation in muscle, liver, and fat cells. When Akt2 fails to respond to insulin, glucose is not cleared from the blood, leading to hyperglycemia. This makes the Akt2 pathway a focus for developing new treatments.

Dysregulation of Akt3 is associated with neurological conditions and cancers of the nervous system. Mutations altering Akt3 activity can affect brain development, with links to conditions like microcephaly or macrocephaly. Because it promotes cell survival, over-activation of Akt3 is also implicated in aggressive brain tumors like glioblastoma, making it a therapeutic target in neurology and oncology.