Cellular life depends on constant communication through complex networks known as signaling pathways. These pathways allow cells to receive external messages, interpret them, and execute an appropriate response, determining the cell’s function or destiny. The Phosphoinositide 3-Kinase (PI3K)-Akt signaling pathway is a major internal regulator that coordinates responses to external cues. It plays a fundamental role in nearly every physiological process, including how a cell decides whether to grow, divide, or survive.
How the PI3K-Akt Pathway Is Activated
The pathway begins when an external signal, typically a growth factor, binds to a Receptor Tyrosine Kinase (RTK) on the cell surface. This binding causes the RTK to change shape and become chemically active, leading to the self-addition of phosphate groups (autophosphorylation). These phosphorylated sites then serve as docking platforms that recruit and activate the enzyme Phosphoinositide 3-kinase (PI3K).
Once recruited to the membrane, PI3K initiates a lipid cascade by acting on the membrane lipid Phosphatidylinositol (4,5)-bisphosphate (PIP2). PI3K adds a phosphate group to convert PIP2 into Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This PIP3 molecule is a second messenger that rapidly accumulates at the inner surface of the cell membrane.
The accumulated PIP3 serves as a specific binding site, recruiting the protein Akt (Protein Kinase B) to the membrane via its Pleckstrin Homology (PH) domain. This membrane localization is the necessary first step for Akt activation. While docked, Akt undergoes dual phosphorylation by two kinases, PDK1 and mTORC2, at specific residues.
This dual phosphorylation fully activates Akt, transforming it into a potent signaling molecule that leaves the membrane to phosphorylate hundreds of other proteins. The enzyme PTEN (Phosphatase and Tensin Homolog) functions as the primary negative regulator, acting as a brake on this process. PTEN directly opposes PI3K by removing the phosphate group from PIP3, converting it back to PIP2 and dismantling the docking site for Akt, thereby stopping the signal.
What the Pathway Controls in the Cell
The newly activated Akt protein travels through the cell, phosphorylating numerous target proteins to carry out three main functional outcomes governing the cell’s fate. A primary function is promoting cell survival by preventing programmed cell death (apoptosis). Akt achieves this by targeting and inactivating the Forkhead box O (FOXO) family of transcription factors.
When Akt is active, it adds phosphate groups to FOXO, causing it to be sequestered in the cytoplasm, outside the nucleus. This action prevents FOXO from entering the nucleus, where it would normally trigger the transcription of genes that initiate cell death. By keeping this pro-death machinery turned off, Akt supports cell survival.
Akt also drives cell growth and proliferation by activating the signaling complex involving the protein mTOR (Mammalian Target of Rapamycin). Akt specifically phosphorylates and inhibits the Tuberous Sclerosis Complex (TSC1-TSC2), which normally inhibits mTOR. This inhibition of the inhibitor leads to the robust activation of mTOR Complex 1 (mTORC1). mTORC1 then initiates processes like protein synthesis and ribosome biogenesis, supplying the components needed for the cell to increase in size and prepare for division.
A third major role is managing cellular metabolism, particularly glucose uptake in response to insulin. In muscle and fat cells, Akt facilitates the movement of the glucose transporter GLUT4 to the cell surface. It does this by phosphorylating a regulatory protein known as AS160 (Akt substrate of 160 kDa). AS160 normally keeps GLUT4 stored inside the cell; Akt’s phosphorylation releases this brake, allowing GLUT4 to rapidly relocate to the plasma membrane to absorb glucose.
When PI3K-Akt Signaling Goes Wrong
The pathway’s tight control over cell survival and growth means that its malfunction is linked to several major diseases, most notably cancer. Uncontrolled activation allows cells to bypass normal regulatory mechanisms, leading to indefinite survival and proliferation. This overactivity frequently results from genetic alterations affecting key components of the cascade.
One common mechanism involves activating mutations in the PIK3CA gene, which codes for PI3K. These mutations cause PI3K to be constantly active, independent of external signals, leading to perpetual production of the activating lipid, PIP3. A second common mechanism is the loss-of-function mutation or deletion of the PTEN gene. Since PTEN is the pathway’s primary “off switch,” its absence leads to an unchecked buildup of PIP3 and persistent Akt activation.
Beyond cancer, the pathway’s disruption underlies metabolic disorders like Type 2 diabetes and conditions involving chronic inflammation. In insulin resistance, the signaling cascade downstream of the insulin receptor is impaired, leading to defective Akt activation in target tissues like muscle and fat. This defect prevents the proper phosphorylation of AS160, inhibiting GLUT4 from moving to the cell surface and resulting in chronically elevated blood glucose levels.
The hyperactivation of the PI3K-Akt pathway in immune cells also contributes to various inflammatory and autoimmune diseases. By promoting the survival and proliferation of specific immune cells, such as T-cells, the pathway can sustain chronic inflammation seen in conditions like rheumatoid arthritis and psoriasis. This survival function, while beneficial in healthy cells, becomes detrimental when dysregulated in tumor and immune cells.
Developing Drugs to Modulate the Pathway
The frequent dysregulation of the PI3K-Akt pathway in numerous cancers has made its components compelling targets for new therapies. This strategy involves using small-molecule inhibitors designed to block the activity of specific proteins within the cascade. By targeting the overactive components, the goal is to stop the abnormal survival and growth signals driving the disease.
Different drugs target distinct nodes in the pathway, offering varied therapeutic approaches. Alpelisib, for example, specifically targets the alpha isoform of PI3K, the enzyme often mutated in breast cancer. By blocking the first step of the cascade, this drug aims to halt the production of PIP3 and subsequent Akt activation.
Moving further downstream, Akt inhibitors like Capivasertib block the activity of the Akt protein itself, inhibiting all three of its isoforms (Akt1, Akt2, and Akt3). This approach is designed to shut down survival and growth signals regardless of whether the initial malfunction occurred at PI3K or through the loss of PTEN. Targeting the final major component, mTOR, can be accomplished with drugs like Everolimus, which inhibit the mTORC1 complex.
Targeting this pathway presents challenges due to its extensive roles in normal physiology, particularly metabolism. For instance, PI3K-alpha inhibition can interfere with the normal insulin signaling needed for glucose uptake, leading to hyperglycemia as a common side effect of drugs like alpelisib. Therefore, therapeutic strategies often involve combining these targeted agents with standard treatments, aiming to maximize anti-tumor effects while managing the metabolic consequences of modulating such a central biological network.