Protein Kinase B, commonly referred to as AKT, is a central regulatory enzyme in cellular biology. It is a serine/threonine-specific protein kinase, meaning it alters the activity of other proteins by attaching phosphate groups to serine and threonine residues. In mammals, AKT exists in three isoforms—AKT1, AKT2, and AKT3—each with slightly different tissue distributions and functions. These isoforms serve as a major hub for information flow, translating external signals related to nutrient availability and growth factors into internal cellular action.
Understanding the Activation Signal
AKT activation begins when the cell receives an external message, such as from a growth factor or insulin, which binds to a surface receptor. This binding triggers the activation of Phosphoinositide 3-kinase (PI3K), an enzyme located inside the cell membrane. PI3K generates a lipid signaling molecule that acts as the direct upstream activator for AKT.
Activated PI3K converts the membrane-bound lipid PIP2 into the lipid messenger PIP3. PIP3 molecules accumulate at the inner plasma membrane, creating a molecular docking site. AKT is recruited to the membrane surface via its Pleckstrin Homology (PH) domain, which specifically binds to the newly generated PIP3. This positioning is essential for its subsequent activation.
Once anchored, AKT requires two separate phosphorylation events to achieve full enzymatic capacity. The first site, Threonine 308 (Thr308), is phosphorylated by PDK1 (Phosphoinositide-Dependent Kinase 1). The second site, Serine 473 (Ser473), is modified by the protein complex mTORC2 (mammalian Target of Rapamycin Complex 2). Phosphorylation at both sites is necessary for AKT to expose its catalytic site and efficiently phosphorylate its downstream target proteins.
Promoting Cell Survival and Growth
A primary function of active AKT is regulating cell fate by promoting survival and preventing programmed cell death, or apoptosis. When survival signals are present, AKT phosphorylates and inactivates molecules that would otherwise initiate the cellular self-destruct mechanism.
For example, AKT phosphorylates the pro-apoptotic protein Bad, causing it to be sequestered in the cytoplasm by binding to the protein 14-3-3, neutralizing its ability to trigger apoptosis. AKT also regulates the Forkhead box O (FOXO) family of transcription factors, which normally activate genes promoting cell death and cell cycle arrest. AKT phosphorylates FOXO factors, retaining them in the cytoplasm and preventing their entry into the nucleus.
Beyond survival, AKT drives cell growth and proliferation by promoting progression through the cell cycle. It achieves this by negatively regulating molecules that normally function as brakes on the cell cycle machinery.
One such brake is the cyclin-dependent kinase inhibitor p27, which prevents the cell from moving from the growth phase (G1) to the DNA synthesis phase (S). AKT phosphorylates p27, causing the inhibitor to be excluded from the nucleus and held inactive in the cytoplasm. The loss of p27 function allows the cell cycle to proceed toward division. AKT also activates the mTORC1 signaling pathway by phosphorylating and inhibiting the tuberous sclerosis complex (TSC2). By removing TSC2’s inhibitory control, AKT stimulates mTORC1, which increases protein synthesis and overall cell mass, a process fundamental to cellular growth.
Controlling Glucose and Energy Metabolism
AKT’s second major function is maintaining energy homeostasis, making it a central component of the body’s response to insulin. Following a meal, insulin signaling activates the PI3K/AKT cascade, particularly the AKT2 isoform, in tissues like skeletal muscle and fat cells. This activation coordinates the rapid uptake and storage of glucose from the bloodstream.
A direct metabolic action of AKT is the regulation of the glucose transporter GLUT4. In the absence of insulin, GLUT4 resides in vesicles inside the cell. Active AKT triggers the translocation of these vesicles to the plasma membrane. Once fused with the cell surface, the exposed GLUT4 transporters facilitate the swift influx of glucose into the cell, which is the primary mechanism by which insulin lowers blood sugar levels.
AKT also influences how the body stores glucose by regulating glycogen synthesis, the conversion of glucose into the storage polymer glycogen. It achieves this by phosphorylating and inactivating Glycogen Synthase Kinase-3 (GSK-3). GSK-3 normally keeps Glycogen Synthase inactive through phosphorylation. When AKT inhibits GSK-3, Glycogen Synthase becomes active, allowing for the rapid synthesis of glycogen for energy storage.
AKT also promotes the cell’s utilization of glucose through glycolysis, the metabolic pathway that breaks down glucose for energy production. It regulates key glycolytic enzymes, such as Hexokinase II. By promoting glucose uptake, storage, and utilization, AKT serves as a primary conductor for the cell’s anabolic response to feeding.
AKT Signaling in Health and Disease
The extensive regulatory reach of AKT means its malfunction is implicated in several major human diseases. When the AKT pathway is excessively active, it drives uncontrolled cell survival and proliferation, a hallmark of many malignancies. This hyperactivation shields cancer cells from apoptosis and promotes unchecked growth.
In numerous human cancers, the AKT pathway is constitutively turned on, often due to genetic alterations in its upstream regulators. Activating mutations in PI3K or the loss of the tumor suppressor PTEN are common ways to keep AKT permanently switched on. Since PTEN normally reverses PI3K action by converting PIP3 back to PIP2, its absence leads to a constant accumulation of the activating lipid messenger. This persistent signaling makes AKT a major therapeutic target in oncology.
Conversely, blunted AKT signaling is a defining feature of certain metabolic disorders, particularly Type 2 Diabetes. In insulin resistance, the signaling cascade from the insulin receptor to AKT is impaired. The resulting decrease in AKT activity, especially the AKT2 isoform, affects the body’s ability to manage glucose effectively. Impaired AKT signaling leads to insufficient GLUT4 translocation to the cell surface in muscle and fat cells, contributing significantly to the elevated blood glucose levels characteristic of Type 2 Diabetes.