The Akt signaling pathway is a fundamental communication system within cells, helping them respond to various external and internal signals. This series of molecular events allows cells to adapt to changes in their environment, impacting their health and function. Understanding this cellular communication helps explain how cells maintain balance and carry out their daily tasks.
The Core Components of Akt Signaling
The Akt signaling pathway begins with an initial signal, often from outside the cell, which activates a protein called Phosphoinositide 3-kinase, or PI3K. PI3K then modifies specific fats on the cell’s inner membrane, creating a docking site for another protein, Akt. Akt, also known as Protein Kinase B (PKB), is recruited to this site, where it becomes activated through a process called phosphorylation.
Once activated, Akt acts as a central coordinator, relaying the signal further into the cell. Akt then influences a broad range of other proteins by adding phosphate groups to them, which can either turn these proteins on or off. A downstream component in this pathway is mTOR (mammalian Target of Rapamycin), which is also influenced by Akt’s activity. This sequential activation, from PI3K to Akt and then to mTOR, resembles a relay race where each component passes the message along, allowing the cell to respond in a coordinated manner.
How Akt Signaling Controls Cellular Functions
Akt signaling plays a broad role in regulating cell growth, division, and maintenance. For example, activated Akt can modify proteins like p21 and p27, which normally halt cell division, thereby promoting cells to enter and progress through the cell cycle.
The pathway also helps cells survive by preventing programmed cell death, a process known as apoptosis. Akt achieves this by inactivating proteins that promote cell death, such as BAD and procaspase-9, and by activating factors that protect the cell. This balance between promoting cell growth and preventing cell death is crucial for healthy tissue maintenance.
Beyond growth and survival, Akt signaling regulates cellular metabolism. It influences how cells take up and use glucose, a primary energy source. Akt can promote the movement of glucose transporters to the cell surface, increasing glucose uptake, and can also stimulate the production of glycogen, a stored form of glucose.
Akt Signaling and Human Health
Dysregulation of the Akt signaling pathway is linked to diseases like cancer and diabetes. In cancer, the Akt pathway often becomes overactive, promoting uncontrolled cell growth and survival. This can occur due to genetic changes, such as mutations or increased copies of genes encoding PI3K or Akt, or the loss of a natural inhibitor protein called PTEN.
When Akt signaling is abnormally high, cancer cells can divide continuously, avoid programmed cell death, and resist therapies. For instance, activated Akt can lead to increased protein and lipid synthesis and enhanced glycolysis, supporting the rapid growth and spread of cancer. This overactivation is a common feature in many types of cancer, including breast, ovarian, prostate, and lung cancers.
In Type 2 diabetes, Akt signaling plays a role in insulin resistance. Insulin normally activates the Akt pathway to facilitate glucose uptake into cells, especially in muscle and fat tissues. However, in insulin resistance, this signaling becomes impaired, leading to reduced glucose uptake and elevated blood sugar levels.
Defects in Akt’s ability to respond to insulin can stem from problems with upstream components or with Akt itself, specifically isoforms like Akt2 and Akt3, which are more involved in glucose metabolism. This impairment means that even when insulin is present, cells do not efficiently absorb glucose, contributing to Type 2 diabetes.
Targeting Akt in Medicine
Understanding Akt signaling’s role in diseases has led to efforts in developing new medical treatments. Researchers are creating drugs to block the pathway’s overactivity, particularly in hyperactive cancers. These drugs are often called ‘Akt inhibitors’ or ‘PI3K/Akt/mTOR inhibitors,’ reflecting the different components they target.
These inhibitors interfere with the activation or function of Akt or its upstream activators like PI3K. For example, some prevent Akt from being recruited to the cell membrane, a necessary step for its activation, while others block its ability to add phosphate groups to other proteins. Several compounds are in clinical development, aiming to selectively shut down problematic overactivity in diseased cells without disrupting normal pathway functions in healthy cells. This targeted approach holds promise for future therapies, particularly in overcoming drug resistance in certain cancers.