The AKT1 gene produces a protein that is a central regulator of cell survival and growth. Learn how its signaling activity is vital for health and how its dysregulation can contribute to human disease.
The AKT1 gene provides instructions for making the AKT1 kinase protein, an enzyme in the serine/threonine kinase family that modifies other proteins. Found in cells throughout the body, AKT1 kinase is a component of signaling pathways that manage cellular activities. It belongs to a family with AKT2 and AKT3, which have distinct but overlapping functions; this article will focus on AKT1.
The AKT1 kinase protein participates in processes fundamental to a cell’s life cycle. It regulates cell growth and division (proliferation), ensuring tissues and organs develop and maintain themselves correctly. The protein also guides cell maturation, where cells develop specialized functions for development and tissue repair.
AKT1 also promotes cell survival by inhibiting apoptosis, the natural process of programmed cell death. While apoptosis eliminates damaged or unneeded cells, AKT1 helps preserve healthy ones. This regulation is important for maintaining tissue stability and function.
AKT1 is involved in cellular metabolism, participating in the insulin signaling pathway to manage glucose. The protein is also influential in the normal development and function of the nervous system. It is thought to contribute to communication between nerve cells and the formation of memories.
The activity of AKT1 is tightly controlled within a major communication route called the PI3K/AKT pathway. This pathway is triggered by external signals, such as growth factors, that bind to receptors on the cell’s surface. This binding initiates a cascade of events inside the cell, leading to the activation of an enzyme called PI3K.
PI3K then produces a molecule that acts as a docking site on the inner surface of the cell membrane, recruiting AKT1 to this location. The primary activation mechanism is phosphorylation, which involves attaching phosphate groups to the protein. For AKT1 to become fully active, it must be phosphorylated at two specific points: Threonine 308 and Serine 473.
Once activated, AKT1 relays signals to downstream targets, including the mTOR protein. The resulting AKT/mTOR signaling pathway controls protein synthesis, which is directly linked to cell growth. To maintain cellular balance, negative regulators like protein phosphatases turn AKT1 off by removing the phosphate groups when the signal is no longer needed.
Alterations in the AKT1 gene or its signaling pathway are associated with several human diseases. These conditions often arise when the balance of cell growth, division, and survival is disrupted. The consequences vary depending on the nature of the genetic change and the cells affected.
Proteus syndrome is a rare condition characterized by patchy overgrowth of bones, skin, and other tissues. This disorder is caused by a specific mutation in the AKT1 gene called Glu17Lys or E17K. This mutation involves the change of a single amino acid in the AKT1 kinase protein, resulting in a protein that is perpetually overactive.
This genetic change is not inherited but occurs randomly in a single cell during early embryonic development. As this cell and its descendants divide, the body becomes a mixture of cells with and without the mutation, a condition known as mosaicism. The overactive AKT1 protein in affected cells drives the uncontrolled, asymmetric overgrowth seen in the syndrome.
Because the mutation is not present in all cells, genetic testing of affected tissue is often required for diagnosis, as it may not be found in a blood sample.
The AKT1 pathway is frequently implicated in cancer due to its role in promoting cell growth and survival. An overactive pathway can allow cells to divide uncontrollably and evade programmed cell death, which are hallmarks of cancer. This dysregulation can happen through mutations in the AKT1 gene or alterations in other genes within the PI3K/AKT pathway.
The E17K mutation found in Proteus syndrome is also found in a small percentage of breast, ovarian, and colorectal cancers. In these cases, the mutation is somatic, meaning it is acquired during a person’s lifetime and is present only in tumor cells. Many other cancers show increased AKT1 protein activity without a specific gene mutation. This overactivation contributes to tumor growth and therapy resistance, making the AKT1 pathway a target for new anticancer drugs.
A possible link has been suggested between the AKT1 gene and schizophrenia, a complex psychiatric disorder. Certain common variations (polymorphisms) in the gene, which involve minor changes in its DNA sequence, occur more frequently in people with schizophrenia than in those without the condition.
How these genetic changes might contribute to schizophrenia risk is not fully understood. Some studies report reduced levels of the AKT1 protein in the brains of individuals with the disorder. The protein is involved in neurodevelopment and brain functions that can be impaired in the condition. The link is considered a risk factor, not a direct cause, and is an area of ongoing investigation.