Within every cell exists a complex network of communication pathways. These signaling pathways transmit instructions from the cell’s surface to its internal machinery, guiding fundamental actions. They are built from proteins that act as molecular messengers, relaying information sequentially to ensure the cell functions correctly.
One of the most studied networks involves two proteins: Akt and mTOR. Akt, also called Protein Kinase B, and mTOR, the mechanistic Target of Rapamycin, are central to a pathway governing basic cellular decisions. This signaling route orchestrates a cell’s response to its environment, and understanding it provides insight into how a cell manages its resources and determines its fate.
The Akt/mTOR Signaling Cascade
The Akt/mTOR signaling pathway is a communication route in eukaryotic cells that translates external cues into internal action. This cascade begins when an external signal, like a growth factor or insulin, binds to a receptor on the cell’s surface. This binding activates the enzyme phosphoinositide 3-kinase (PI3K), which generates a docking site on the inner cell membrane that recruits proteins with a pleckstrin-homology domain.
Akt is one of the proteins recruited to this site. At the membrane, Akt is partially activated by another protein, PDK1, which phosphorylates it at Threonine 308. Full activation requires a second phosphorylation at Serine 473, a task performed by mTOR Complex 2 (mTORC2). This two-step process ensures Akt is only activated when appropriate upstream signals are present.
Once fully activated, Akt moves into the cell’s interior and acts as a kinase, an enzyme that adds phosphate groups to other proteins. One of its primary targets is the tuberous sclerosis complex (TSC1/TSC2), which normally keeps mTOR inactive. Akt phosphorylates and inhibits the TSC complex, which releases the protein Rheb to bind to and activate the main mTOR complex, mTORC1.
This sequence from the cell surface to mTORC1 activation is a carefully regulated cascade. Each step provides a control point, ensuring the cell’s growth and metabolic machinery is engaged only under the right conditions. The pathway also includes inhibitors, like the tumor suppressor PTEN, which reverses PI3K’s action to prevent unwanted activation. The precision of this cascade is central to maintaining cellular order.
Regulating Cellular Growth and Proliferation
When the Akt/mTOR pathway activates mTORC1, it initiates a program to increase cell size and promote division. Activated mTORC1 directly targets the machinery responsible for building new cellular components. A primary function is promoting protein synthesis by phosphorylating downstream effectors like ribosomal protein S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1).
Phosphorylating S6K enhances the production of ribosomes, while the phosphorylation of 4E-BP1 causes it to release its hold on the factor eIF4E. This frees eIF4E to initiate the translation of messenger RNA into protein. This coordinated action increases the cell’s capacity to produce the proteins needed for it to grow larger, a process known as hypertrophy. This increase in size is a prerequisite for a cell to eventually divide.
The pathway also directly influences cell proliferation. Akt contributes to this by phosphorylating and inhibiting cell cycle suppressors like p21 and p27. These proteins act as brakes on the cell cycle, and by inhibiting them, Akt helps the cell move through the different phases of division.
The pathway also supports synthesizing other building materials, such as lipids. Akt activates enzymes like ATP-citrate lyase, which helps produce acetyl-CoA, a building block for fatty acids. This ensures the growing cell has enough lipids to construct new membranes. This control over synthesizing proteins and lipids demonstrates how the pathway orchestrates both cell growth and division.
Controlling Metabolism and Nutrient Sensing
The Akt/mTOR pathway regulates cellular metabolism, acting as the cell’s sensor for nutrient availability. Its activity is tied to the presence of energy sources and building blocks, particularly glucose and amino acids. When these nutrients are abundant, the pathway becomes active, signaling that conditions are favorable for energy consumption, storage, and growth.
When nutrients are plentiful, activated mTORC1 directs metabolic processes toward anabolism, the construction of complex molecules. It promotes a shift in glucose metabolism toward glycolysis, which is advantageous for a growing cell because it provides intermediates for building other molecules, like nucleotides for DNA replication. mTORC1 achieves this partly by increasing the translation of the transcription factor HIF1α, which drives the expression of glycolytic enzymes.
The pathway is also sensitive to the levels of amino acids. Their availability is required for mTORC1 activation, which ensures the cell only commits to the energy-intensive process of protein synthesis when all necessary components are available. This prevents wasteful production. Akt also plays a role in glucose uptake by stimulating glucose transporters to move to the cell surface. This action is important for insulin signaling, which manages blood glucose levels.
Consequences of Pathway Dysregulation
Improper activation of the Akt/mTOR pathway is a hallmark of several human diseases. When the signaling cascade becomes persistently active, it can drive cells to grow and divide without restraint, contributing to the development of cancer. This overactivation can occur due to mutations in genes coding for pathway proteins, such as PI3K or Akt, or the loss of inhibitors like PTEN. In many cancers, including breast, prostate, and ovarian, this pathway is hyperactive.
A constant “on” signal from a dysregulated pathway gives cancer cells an advantage. It promotes growth and supports the metabolic reprogramming that allows tumor cells to thrive, which includes the enhanced glucose uptake and glycolysis known as the Warburg effect. The pathway’s promotion of protein and lipid synthesis also provides the raw materials for new cancer cells.
Beyond cancer, pathway malfunction is linked to metabolic disorders. Because the pathway mediates insulin signaling, its dysregulation can contribute to type 2 diabetes and obesity. Chronic overactivation, often from overnutrition, can lead to insulin resistance, where cells no longer respond effectively to insulin. This chronic signaling can also lead to excessive fat storage in tissues, contributing to obesity. The pathway’s role as a nutrient sensor becomes a liability when nutrients are constantly in excess, leading to metabolic imbalance.