AKT, also known as Protein Kinase B (PKB), represents a family of three serine/threonine-specific protein kinases that serve as central signaling molecules within cells. These proteins are fundamental to maintaining cellular balance and responding to various internal and external cues. AKT’s broad influence stems from its ability to modify the activity of numerous other proteins through a process called phosphorylation, which involves adding a phosphate group. This molecular switch allows AKT to orchestrate a wide array of cellular activities.
Understanding AKT’s Core Functions
AKT isoforms, specifically AKT1, AKT2, and AKT3, contribute to essential cellular processes. AKT1 is recognized for its role in cellular survival, inhibiting programmed cell death (apoptosis). It also participates in pathways that induce protein synthesis, important for overall tissue growth and the development of skeletal muscle.
AKT’s influence extends to cell proliferation. It helps regulate the cell cycle, ensuring cells divide appropriately when needed. This function is important for tissue repair and normal development. AKT also plays a part in cell migration, allowing cells to move to specific locations.
Beyond growth and division, AKT is involved in cellular metabolism. AKT2, in particular, is needed for the movement of glucose transporter 4 (GLUT4) to the cell membrane, important for glucose uptake in response to insulin. AKT also influences glycogen synthesis in the liver and muscles, storing glucose for energy. This metabolic control ensures cells have the necessary energy and building blocks.
How AKT Activity is Regulated
The activity of AKT is controlled by upstream signals, primarily through the Phosphoinositide 3-kinase (PI3K) pathway. When growth factors or hormones bind to receptors on the cell surface, they activate PI3K. Activated PI3K then produces the lipid phosphatidylinositol (3,4,5) trisphosphate (PIP3) at the cell membrane.
PIP3 acts as a docking site, recruiting inactive AKT to the plasma membrane. Once at the membrane, AKT undergoes a two-step phosphorylation process. First, 3-phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates AKT at a threonine residue. Following this, other proteins, such as mammalian target of rapamycin complex 2 (mTORC2), phosphorylate AKT at a serine residue, leading to its full activation.
Phosphatases, such as PTEN, counteract the action of PI3K. PTEN removes the phosphate group from PIP3, converting it back to phosphatidylinositol (3,4) bisphosphate (PIP2). This dephosphorylation by PTEN reduces the amount of PIP3 available, thereby attenuating AKT activation. This control of AKT activation and deactivation is important for maintaining normal cellular functions.
AKT’s Role in Disease Progression
Dysregulation of AKT, whether through overactivity or underactivity, can contribute to the development and progression of various diseases. AKT plays a prominent role in cancer, where its hyperactivation can drive uncontrolled cell growth, enhanced cell survival, and resistance to therapies. Elevated AKT activity has been observed in many cancer types, including breast, prostate, and lung cancers. This overactivity often results from mutations or alterations in upstream regulators like PI3K or the loss of PTEN function.
When AKT is hyperactive in cancer cells, it promotes cell survival by inhibiting proteins that trigger apoptosis and enhancing anti-apoptotic signals. It also stimulates cell cycle progression and can promote metastasis by regulating proteins involved in cell migration and invasion. For instance, AKT can inactivate glycogen synthase kinase 3 beta (GSK3β), which promotes cell cycle progression.
Beyond cancer, AKT dysregulation is also implicated in metabolic disorders like insulin resistance and type 2 diabetes. Impaired AKT activation is a hallmark of insulin resistance, leading to reduced glucose uptake in muscles and increased glucose production in the liver. This disruption of glucose metabolism can contribute to high blood sugar levels. In visceral obesity, the AKT-mediated insulin signaling pathway can be inhibited, leading to increased fat breakdown and further metabolic disorders.
AKT’s involvement extends to neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. While the exact mechanisms are complex, AKT regulates neuronal toxicity and is involved in signaling pathways that mediate neuronal survival. Dysregulation of the PI3K/AKT signaling pathway, including the hyperactivity of downstream enzymes like GSK3, contributes to the formation of toxic protein aggregates, which are characteristics of Alzheimer’s disease.
Therapeutic Approaches Targeting AKT
Given AKT’s widespread involvement in disease, it has become an important target for therapeutic intervention, particularly in cancer treatment. The development of AKT inhibitors aims to block its activity, thereby disrupting the uncontrolled growth and survival of cancer cells. These inhibitors can be designed to compete with ATP for binding to AKT’s active site or to bind to other sites on the protein to alter its function.
Several AKT inhibitors have undergone testing in clinical trials, both alone and in combination with chemotherapy or hormonal agents. The rationale behind these approaches is to halt tumor progression and overcome drug resistance often associated with hyperactive AKT. While some trials have shown promising results, challenges remain in developing effective and specific drugs.
One challenge lies in the complexity of the AKT signaling network and the potential for cancer cells to develop alternative signaling pathways to bypass AKT inhibition, leading to resistance. Another consideration is achieving sufficient specificity to avoid widespread side effects, as AKT plays many normal functions in healthy cells. Ongoing research focuses on identifying reliable biomarkers to predict which patients will respond best to AKT-targeted therapies and exploring new combination strategies to enhance their effectiveness.