Other meanings of PI3K/AKT pathway
Cell biology
The PI3K/AKT pathway is an intracellular signaling pathway regulating cell survival, growth, and metabolism. It converts signals from hormones, growth factors, and extracellular matrix into coordinated changes in gene expression, protein synthesis, nutrient use, and resistance to cell death. Abnormal activation is common in cancer and contributes to metabolic and developmental disorders.
The pathway begins when an activated receptor recruits phosphoinositide 3-kinase, or PI3K, to the inner surface of the plasma membrane. Class I PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), a short-lived docking signal. PIP3 attracts AKT and the kinase PDK1 through their pleckstrin-homology domains; PDK1 and mTORC2 then phosphorylate AKT at sites needed for full activity.1
Activated AKT regulates many substrates rather than acting as a single linear switch. It inhibits pro-apoptotic proteins, stimulates glucose uptake and glycogen synthesis, and promotes protein production partly through the mTORC1 complex. The lipid phosphatase PTEN reverses the initiating reaction by converting PIP3 back toward PIP2, thereby restraining signal duration and intensity.2
The pathway coordinates cell growth with the availability of nutrients, mitogenic signals, and energy. Insulin and insulin-like growth factor receptors are prominent upstream activators, while receptor tyrosine kinases, G-protein-coupled receptors, integrins, and some cytokine receptors can also engage PI3K. AKT promotes survival partly by suppressing apoptotic signaling and supports metabolism by influencing glucose transport, lipid synthesis, and mitochondrial functions.1
Signal control is distributed across several feedback loops. mTORC1 can inhibit upstream insulin-receptor signaling through S6 kinase, whereas cellular stress and low energy activate AMPK, which constrains anabolic growth. The pathway also communicates with RAS–MAPK signaling, so cells may preserve proliferation through parallel routes when one branch is inhibited.3 This context dependence explains why the same pathway can produce different effects in muscle, liver, neurons, immune cells, and epithelial tissues.
Persistent PI3K/AKT signaling can help cells evade apoptosis, grow without normal external cues, alter metabolism, and acquire treatment resistance. Cancer-associated changes include activating mutations in PIK3CA, amplification or mutation of AKT, loss of PTEN, and altered receptor signaling; these changes occur across breast, colorectal, endometrial, and other cancers.2
Therapeutic inhibitors target different levels of the network. Alpelisib selectively inhibits the p110α isoform of class I PI3K and is used for certain PIK3CA-mutated, hormone-receptor-positive advanced breast cancers, in combination with endocrine therapy.4 Other approaches inhibit AKT or mTOR, but resistance can arise through pathway reactivation, compensatory receptor signaling, or parallel MAPK signaling. Toxicities such as hyperglycemia, rash, diarrhea, and stomatitis reflect the pathway’s normal physiological functions.
The PI3K family is broader than the canonical growth signal usually meant by “PI3K/AKT.” Class I PI3Ks produce PIP3 and most directly activate AKT, whereas class II enzymes generate distinct phosphoinositide pools and class III PI3K Vps34 participates in endosomal trafficking and autophagy.2 AKT itself has three closely related isoforms—AKT1, AKT2, and AKT3—with partly overlapping but tissue-biased functions.
Spatial organization is another overlooked feature: signaling can differ at the plasma membrane, endosomes, mitochondria, and nucleus. PIP3 is rapidly removed by PTEN and the inositol polyphosphate 4-phosphatases, making local lipid concentration and timing biologically significant. Some tumors depend on non-AKT outputs of PI3K, including RAC activation or vesicle trafficking, so blocking AKT alone does not necessarily silence the entire PI3K network.3
The pathway is often written PI3K–AKT–mTOR because mTOR is a major downstream effector, although PI3K and AKT also regulate outputs independent of mTOR.
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