The AKT protein, also known as Protein Kinase B (PKB), is a fundamental component within the intricate machinery of our cells. It functions as a central signaling molecule, influencing a wide array of cellular processes. Understanding AKT’s role provides insight into how cells maintain normal function and how disruptions can contribute to various health conditions.
Understanding AKT Protein
The AKT protein is an enzyme categorized as a serine/threonine kinase. Kinases are specialized enzymes that perform a crucial action within cells: they add phosphate groups to other proteins. This process, known as phosphorylation, acts like an on-off switch, either activating or deactivating the target proteins and thereby regulating their function.
There are three isoforms of AKT found in mammalian cells: AKT1, AKT2, and AKT3. While these isoforms are structurally similar, their specific roles and expression patterns can vary across different tissues and cellular contexts. AKT proteins act as key intermediaries in cellular communication networks throughout the cell.
Central Regulator of Cellular Activities
AKT functions as a central hub, orchestrating fundamental cellular activities. One of its main roles is promoting cell survival by preventing programmed cell death (apoptosis). AKT achieves this by phosphorylating and inhibiting pro-apoptotic proteins such as BAD and caspase-9, while also promoting the expression of anti-apoptotic proteins like BCL-2 and BCL-xL.
Beyond survival, AKT significantly influences cell growth and proliferation. It regulates these processes by activating downstream targets like mTOR (mechanistic target of rapamycin), an important regulator of protein synthesis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2, thereby activating the mTORC1 signaling pathway.
AKT also plays a role in cellular metabolism, impacting how cells process and utilize energy. For instance, AKT2 is particularly involved in glucose metabolism, facilitating the uptake of glucose into cells. It does this by promoting the movement of glucose transporter 4 (GLUT4) to the cell surface in response to insulin signaling, allowing glucose to enter the cell.
AKT’s Role in Human Health and Disease
When AKT does not function correctly, either by being overly active or underactive, it can contribute to the development and progression of various diseases. A significant area where AKT dysregulation is observed is in cancer. In many cancer types, the AKT pathway is constitutively activated. This sustained activation provides cancer cells with advantages such as uncontrolled growth, enhanced survival, and resistance to therapies.
The hyperactivation of AKT can stem from mutations in upstream regulatory proteins, such as PI3K, or the loss of tumor suppressor proteins like PTEN. For example, AKT1 activation is linked to cellular survival pathways, inhibiting processes that lead to cell death. In breast cancer, genetic alterations in AKT1 are significantly enriched in metastatic cases, highlighting its role in tumor progression.
AKT’s involvement in metabolic disorders is also notable, particularly in type 2 diabetes. Its role in insulin signaling and glucose metabolism means that dysregulation can impair the body’s ability to regulate blood sugar levels. For instance, impaired AKT activity can lead to reduced glucose uptake in muscle and fat cells, contributing to insulin resistance.
Targeting AKT for Therapeutic Development
Given its widespread influence on cellular processes and its involvement in various diseases, AKT has become an important target for therapeutic development. Researchers are developing AKT inhibitors, drugs designed to block or reduce its activity in conditions where it is overactive, such as cancer. These inhibitors aim to counteract the uncontrolled cell growth and survival that characterize many tumors.
Developing effective AKT inhibitors presents challenges, including achieving specificity for certain AKT isoforms or avoiding off-target effects that could disrupt normal cellular functions. Despite these hurdles, ongoing research explores various strategies, including ATP-competitive and allosteric inhibitors, which block its activity by binding to different sites. The potential for combining AKT inhibitors with other therapies, such as chemotherapy or immunotherapy, is also being investigated to enhance treatment effectiveness and overcome drug resistance in cancer.