pi3K

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3' hydroxyl group of phosphatidylinositol lipids on the inner surface of the cell membrane. The best-characterized reaction converts PI(4,5)P2 to PI(3,4,5)P3 (PIP3), a lipid second messenger that recruits proteins with pleckstrin homology (PH) domains, such as AKT and PDK1, to the membrane to regulate signaling pathways controlling growth, survival, metabolism, and migration.

PI3Ks are divided into three classes. Class I is the best studied in humans and is further subdivided into IA (p110α, p110β, p110δ with regulatory subunits like p85) and IB (p110γ with regulatory subunits). Class I enzymes are activated by receptor tyrosine kinases (RTKs) or G-protein-coupled receptors and primarily generate PIP3 at the plasma membrane. Class II and Class III enzymes participate in vesicle trafficking and autophagy, with Class III (Vps34) producing PI(3)P and Class II acting on PI(4)P and PI(5)P.

Physiologically, PI3K signaling influences cell growth, metabolism, survival, and immune function. Isoform expression patterns contribute to tissue-specific effects, with PI3Kα and PI3Kβ broadly expressed, and PI3Kδ and PI3Kγ enriched in leukocytes. Dysregulation of the pathway is common in cancer and other diseases, leading to development of targeted inhibitors.

Therapeutically, selective inhibitors targeting Class I PI3Ks include idelalisib (PI3Kδ), alpelisib (PI3Kα), duvelisib (PI3Kδ/γ), and copanlisib (PI3Kα/β). These agents aim to suppress aberrant signaling but can cause adverse effects such as hyperglycemia, rash, and infections, requiring careful clinical management.