How the Akt ERK Pathway Drives Growth, Division, and Disease

Within every cell of the body exists a complex communication network of signaling pathways, which function like relay races passing information from the cell’s surface to its interior. These pathways allow cells to respond to countless cues from their environment and from each other, coordinating everything from growth to metabolism. The process often starts when a molecule, like a hormone or growth factor, binds to a specific receptor protein on the cell’s surface. This signal then activates other molecules in a domino-like effect until the final molecule is activated and a specific job inside the cell is carried out. The Akt and ERK pathways are two prominent examples of these cellular communication lines, each playing a distinct role.

Meet Akt and ERK: The Cell’s Key Messengers

At the heart of their respective pathways are two proteins: Akt and ERK. These belong to a specialized class of enzymes known as kinases. The primary job of a kinase is to act like a molecular switch by adding a small chemical tag, a phosphate group, to other proteins—a process called phosphorylation. This action can turn a target protein “on” or “off,” effectively passing a message along the signaling chain.

Akt, also known as Protein Kinase B (PKB), and ERK, which stands for Extracellular signal-Regulated Kinase, are central hubs in this cellular information network. They receive signals from upstream molecules and, in turn, activate a host of downstream targets. Think of them as key managers in a factory, taking instructions from the main office and directing different teams on the factory floor to perform specific tasks.

The Akt Pathway: Fueling Cell Growth and Survival

The Akt pathway is a communication route inside cells that primarily manages growth, metabolism, and survival. Its activation often begins when external signals, such as growth factors or hormones like insulin, connect with receptors on the cell’s surface. This binding event triggers another enzyme, called PI3K (phosphoinositide 3-kinase), which then creates a docking site on the inner side of the cell membrane that recruits and switches on Akt.

Once activated, a major function of Akt is to promote cell survival by switching off proteins that would otherwise instruct the cell to undergo programmed cell death, a process called apoptosis. Akt also helps a cell to grow in size, not just to divide.

This pathway also has a significant impact on the cell’s metabolism. For instance, in response to insulin, the Akt pathway helps facilitate the uptake and use of glucose from the bloodstream. By activating another protein complex known as mTORC1, Akt boosts the production of proteins and lipids needed for a cell to increase in size.

The ERK Pathway: Directing Cell Division and Specialization

The ERK pathway, frequently called the MAPK/ERK pathway, is a signaling chain most commonly associated with promoting cell division, known as proliferation. Its activation sequence is a classic example of a kinase cascade, where one kinase activates another in a stepwise fashion. The process begins when a growth factor binds to a receptor, which then activates a protein called Ras.

Ras, when active, recruits and turns on a kinase named Raf. Raf then phosphorylates and activates the next kinase in line, MEK, and finally, MEK activates ERK. This step-by-step activation allows the cell to amplify the initial signal, ensuring a robust response.

Once active, ERK moves into the cell’s nucleus, where it can phosphorylate transcription factors—proteins that control which genes are turned on or off. By doing so, ERK can command the cell to produce the proteins needed to enter the cell cycle and divide. While the Akt pathway focuses more on increasing cell size, the ERK pathway’s primary output is to increase the number of cells, and it also plays a part in cell differentiation.

When Signaling Goes Wrong: Akt/ERK in Disease

For an organism to remain healthy, the activity of the Akt and ERK pathways must be precisely regulated. When this control system breaks down and these pathways become stuck in the “on” position, it can lead to disease. The constant signaling for growth and survival is a hallmark of many human cancers.

In numerous types of cancer, including breast, lung, and prostate, mutations in the genes that code for proteins in these pathways are common. For example, mutations in Ras proteins, which activate the ERK pathway, are found in about 30% of all human cancers. Similarly, mutations that cause overactivation of PI3K or Akt, or the loss of natural inhibitors like the PTEN protein, drive the uncontrolled growth of cancer cells.

While cancer is the most prominent disease linked to Akt and ERK dysregulation, it is not the only one. Because the Akt pathway is so closely tied to insulin signaling, its malfunction can contribute to metabolic disorders like type 2 diabetes. Problems in these signaling networks are also being investigated for their roles in cardiovascular and neurological diseases.

Targeting Akt/ERK: Avenues for New Treatments

The role of the Akt and ERK pathways in driving cancer has made them prime targets for the development of new therapies. Researchers have developed a class of drugs known as kinase inhibitors, which are small molecules designed to interfere with specific components of these pathways. These drugs can be designed to block Akt, MEK, or ERK directly, preventing them from passing on their growth-promoting messages.

Several inhibitors targeting these pathways have been approved for clinical use, particularly for cancers with specific genetic mutations. For example, MEK inhibitors are used to treat certain types of melanoma that are driven by mutations in the Raf protein. This approach represents a shift toward more personalized medicine, where treatment is tailored to the specific molecular drivers of a patient’s disease.

Despite these successes, developing these therapies presents challenges. Because Akt and ERK are also used by healthy cells, blocking them can cause side effects. Cancer cells can be resourceful and may develop resistance to these drugs by finding alternative signaling routes, so ongoing research focuses on creating more precise inhibitors and using them in combination with other treatments.