Akt, also known as Protein Kinase B, operates as a central regulatory enzyme within our cells. This protein acts like a master switch, orchestrating a wide array of fundamental life processes. Its proper function is integral to how cells grow, survive, and adapt to their environment, making it a significant component of cellular communication networks.
The PI3K/Akt Signaling Pathway
Akt activation begins with external signals. Growth factors, such as insulin, bind to specific receptor proteins on the cell’s outer surface. This binding triggers a cascade, activating Phosphoinositide 3-kinase (PI3K).
Once activated, PI3K adds a phosphate group to phosphatidylinositol 4,5-bisphosphate (PIP2), converting it into phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 then accumulates at the inner surface of the cell membrane, acting as a unique docking site.
PTEN (Phosphatase and Tensin Homolog) counterbalances this system. PTEN functions as a “brake” by removing the phosphate group from PIP3, converting it back to PIP2. This enzymatic action by PTEN helps to limit the amount of PIP3 available, thereby preventing uncontrolled signaling and maintaining cellular balance. The balance between PI3K creating PIP3 and PTEN degrading it ensures the Akt activation signal is tightly controlled.
The Mechanics of Activation
With PIP3 at the cell membrane, Akt is recruited. Akt possesses a specialized pleckstrin homology (PH) domain that recognizes and binds to PIP3. This binding causes Akt to change shape, making it accessible to other modifying enzymes.
Full activation of Akt requires two distinct phosphorylation events. The first phosphorylation occurs at a site called Threonine 308 (Thr308), located within Akt’s activation loop. This modification is carried out by phosphoinositide-dependent kinase-1 (PDK1), which also binds to PIP3 at the membrane.
The second phosphorylation happens at Serine 473 (Ser473). This site is phosphorylated by the mechanistic Target of Rapamycin Complex 2 (mTORC2). While Thr308 phosphorylation significantly boosts Akt’s activity, Ser473 phosphorylation further enhances and stabilizes its full activation. Both sites must be modified for Akt to achieve maximal function.
Cellular Functions of Activated Akt
Once fully activated, Akt influences diverse cellular processes. One of its main roles is promoting cell survival by inhibiting programmed cell death, a process known as apoptosis. Akt achieves this by phosphorylating and inactivating various proteins that normally promote cell death, helping cells to persist and maintain tissue integrity.
Akt also plays a role in stimulating cell growth and proliferation. It influences proteins like the mechanistic Target of Rapamycin (mTOR) complex 1 (mTORC1). Akt phosphorylation of targets like TSC2 (Tuberous Sclerosis Complex 2) leads to the activation of mTORC1, which then promotes protein synthesis and overall cell size increase.
Beyond growth, Akt regulates cellular metabolism, particularly glucose uptake and utilization. Activated Akt facilitates the movement of glucose transporters, such as GLUT4, to the cell surface. This translocation allows cells to absorb more glucose from the bloodstream. By influencing enzymes involved in glucose metabolism, Akt helps cells efficiently manage their energy resources, ensuring a steady supply for various cellular functions.
Dysregulation in Disease
When the sophisticated Akt activation system malfunctions, it can contribute to various diseases. A common problem is Akt over-activation, often due to genetic alterations within the pathway. For instance, mutations in the PI3K gene can lead to its constant “on” state, or a loss of function in the PTEN gene (which normally acts as a “brake”) can result in unchecked PIP3 accumulation.
Persistent Akt activation is a hallmark of many cancers. With Akt constantly signaling for cell survival and proliferation, cancer cells gain an advantage, resisting programmed cell death and growing uncontrollably. This unchecked growth and survival contribute to tumor formation and progression. Approximately 39% of diverse human cancers show aberrations in the PI3K/Akt/mTOR pathway, including PIK3CA mutations or PTEN loss.
Beyond cancer, Akt dysregulation is implicated in metabolic diseases, such as type 2 diabetes. In these conditions, cells can become resistant to insulin, leading to impaired Akt signaling. This impairment reduces the ability of cells to properly take up glucose, contributing to high blood sugar levels characteristic of diabetes. Understanding these dysregulations offers avenues for developing targeted therapies to restore proper cellular function.