Protein Kinase B (PKB), also known as Akt, is a central molecular switch found within virtually all mammalian cells. This enzyme is a serine/threonine-specific protein kinase, meaning its job is to attach phosphate groups to specific serine or threonine amino acids on other proteins. By adding these chemical tags, PKB acts as a regulator, controlling signaling pathways that dictate a cell’s destiny. The kinase integrates external signals from growth factors and hormones to manage fundamental cellular processes, coordinating cell survival, growth, and metabolic state.
Identity and Isoforms
PKB is a family of three distinct isoforms, each encoded by a separate gene: Akt1 (PKB\(\alpha\)), Akt2 (PKB\(\beta\)), and Akt3 (PKB\(\gamma\)). All three share structural similarity, featuring a Pleckstrin Homology (PH) domain, a central kinase domain, and a C-terminal regulatory domain. Despite this common architecture, the isoforms are not interchangeable and exhibit different tissue distribution patterns.
Isoform Specialization
Akt1 is expressed everywhere and is linked to cell survival and overall body growth. Akt2 is prominent in insulin-responsive tissues like skeletal muscle, liver, and fat, regulating glucose metabolism. Akt3 is mainly found in the brain and testes, playing a role in neuronal development. This specialization means the three isoforms have partially non-redundant roles in the body’s physiology.
How Activation Occurs
PKB normally rests in an inactive state within the cytosol, waiting for a signal. The primary signal triggering activation comes from growth factors or hormones like insulin binding to cell surface receptors. This binding activates Phosphoinositide 3-Kinase (PI3K). PI3K produces a signaling lipid, Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), directly on the inner cell membrane.
PKB possesses the PH domain, which binds specifically to PIP3. This binding recruits PKB from the cytosol to the cell membrane, positioning it for activation. Full activation requires two specific phosphorylation steps. The first is performed by Phosphoinositide-Dependent Kinase-1 (PDK1) at threonine 308 (T308), providing partial activity. The second phosphorylation occurs at serine 473 (S473) and is carried out by mTOR Complex 2 (mTORC2), leading to full activity. Once these two events occur, PKB is fully active and ready to move away from the membrane to phosphorylate its target proteins throughout the cell.
The Core Functions of PKB
The central role of activated PKB is to promote cellular growth and survival by regulating numerous downstream targets.
Cell Survival
PKB orchestrates cell survival by preventing apoptosis, or programmed cell death. It achieves this by attaching phosphate groups to pro-apoptotic proteins, such as BAD and Forkhead box O (FOXO) transcription factors, effectively inactivating them. By inhibiting these pro-death signals, PKB ensures the cell remains viable.
Growth and Proliferation
PKB promotes cell growth and proliferation by acting upon the mTOR signaling pathway, a regulator of protein synthesis and cell size. PKB phosphorylates and inactivates the TSC1-TSC2 complex, a negative regulator of the mTOR pathway. Removing this inhibitory brake activates mTOR, accelerating the production of proteins and lipids necessary for cell division and increased size.
Metabolic Regulation
PKB is a major player in metabolic regulation, particularly in response to insulin signaling the body to store energy. Activated PKB promotes glucose uptake into muscle and fat cells by triggering the movement of glucose transporters, such as GLUT4, to the cell surface. PKB also enhances energy storage by inactivating glycogen synthase kinase-3 (GSK-3), which allows for the synthesis of glycogen, the storage form of glucose.
PKB and Human Disease
Dysregulation of PKB signaling is strongly linked to several serious human diseases due to its broad influence over cell survival, growth, and metabolism.
PKB and Cancer
In cancer, the PKB pathway is frequently overactive, which provides a survival advantage to tumor cells. This hyperactivation is often caused by mutations in upstream regulators, such as constantly active PI3K or the loss of the tumor-suppressing protein PTEN, which normally inhibits PKB signaling. The resulting unchecked PKB activity drives uncontrolled cell proliferation and shields cancer cells from death signals.
PKB and Type 2 Diabetes
The pathway’s central role in energy management also implicates it in metabolic disorders like Type 2 diabetes. In conditions of insulin resistance, the signaling cascade leading to PKB activation in muscle and fat cells becomes impaired. Diminished PKB signaling means glucose transporters are not efficiently moved to the cell membrane, leading to reduced glucose uptake from the blood. This failure to clear glucose contributes to the chronically high blood sugar levels characteristic of Type 2 diabetes. The strong connection between PKB and these major diseases has made the kinase a focus for therapeutic research aimed at developing targeted inhibitors.