Protein kinase B, commonly known as AKT, is an enzyme that serves as a central point for receiving and relaying signals within a cell. It belongs to the serine/threonine protein kinase family, modifying other proteins by adding phosphate groups to specific serine or threonine amino acids. AKT integrates information from outside the cell to regulate fundamental processes governing cell life and death. Its finely tuned activity determines whether a cell should grow, divide, survive, or initiate programmed cell death.
Defining the AKT Protein and Its Signaling Pathway
AKT is a collective name for three highly similar protein isoforms in mammals: AKT1, AKT2, and AKT3. These proteins share a conserved structure, including an N-terminal Pleckstrin Homology (PH) domain for binding to cell membrane lipids, and a central kinase domain that performs the catalytic function of adding phosphate groups.
AKT is a key component of the PI3K/AKT/mTOR axis, the most important cell communication system for growth and survival. This pathway begins when external cues, such as growth factors or hormones, bind to cell surface receptors, activating Phosphoinositide 3-kinase (PI3K). PI3K generates the lipid messenger PIP3 at the inner cell membrane. AKT is recruited to this location, where it is activated to relay the signal into the cell’s interior.
The Mechanisms of AKT Activation
AKT activation is a highly controlled process requiring two distinct steps for full function. The initial step involves the translocation of inactive AKT from the cytoplasm to the plasma membrane. This movement occurs when AKT’s PH domain binds directly to the PIP3 molecules generated by PI3K.
Once anchored, AKT undergoes two separate phosphorylation events necessary for its catalytic activity. The first occurs at Threonine 308 (Thr308) within the kinase domain’s activation loop, carried out by the enzyme PDK1 (Phosphoinositide-Dependent Kinase-1).
The second phosphorylation happens at Serine 473 (Ser473) in the C-terminal regulatory domain, primarily performed by the mTOR complex 2 (mTORC2). Simultaneous phosphorylation at both sites causes a conformational change that relieves auto-inhibition. This results in a fully active enzyme that detaches from the membrane and moves into the cell to phosphorylate its target proteins.
Crucial Roles in Cell Survival and Metabolism
Activated AKT promotes cell survival and regulates nutrient use, maintaining the health and function of normal cells. It acts as an anti-apoptotic signal, preventing programmed cell death by phosphorylating and inactivating pro-apoptotic proteins like BAD. This action allows cells to survive mild stresses and maintain tissue integrity.
AKT is also a central regulator of cellular metabolism, particularly glucose handling. The AKT2 isoform is required for insulin signaling to induce the translocation of the glucose transporter protein GLUT4 to the cell membrane. This process allows muscle and fat cells to rapidly absorb glucose from the bloodstream, helping to maintain stable blood sugar levels.
The enzyme further influences metabolism by promoting the synthesis of large molecules necessary for growth. It activates the mTOR Complex 1 (mTORC1) signaling pathway, often by inhibiting the TSC1/TSC2 protein complex. Active mTORC1 drives increased protein synthesis and cell growth, which is necessary for tissue repair. AKT also promotes glycogen synthesis by inactivating Glycogen Synthase Kinase 3-beta (GSK3-beta).
The Involvement of AKT in Human Pathology
Loss of tight control over AKT activation allows its pro-growth and anti-death signals to contribute to disease. Hyperactivation of the PI3K/AKT/mTOR pathway is one of the most common molecular abnormalities observed across a wide spectrum of human cancers. This chronic activation often stems from genetic defects, such as activating mutations in the PI3K gene or the loss or mutation of the tumor suppressor protein PTEN.
PTEN normally acts as a brake on the pathway by dephosphorylating the lipid messenger PIP3, which prevents AKT from localizing to the membrane and becoming active. When PTEN is absent or non-functional, the buildup of PIP3 leads to uncontrolled AKT activation. This hyperactivity promotes uncontrolled proliferation, enhances survival by blocking apoptosis, and often leads to resistance against chemotherapy and radiation treatments.
AKT dysfunction is also implicated in metabolic disorders, particularly insulin resistance and Type 2 Diabetes. In these conditions, the insulin signaling cascade is impaired, leading to insufficient AKT activation. This diminished activity in muscle and fat cells prevents the proper translocation of GLUT4 transporters, resulting in poor glucose uptake and persistently high blood sugar levels.
Due to AKT’s involvement in these major diseases, it has become a significant target for drug development. Researchers are actively developing specific AKT inhibitors designed to block the enzyme’s activity where it is aberrantly overactive. These targeted therapies aim to selectively shut down hyperactive survival signals in cancer cells or correct metabolic imbalances.