PI3kinase

PI3 kinases, or phosphoinositide 3-kinases (PI3Ks), are a family of lipid kinases that phosphorylate the 3-position of the inositol ring of phosphatidylinositol lipids. The primary reaction converts PI(4,5)P2 to PI(3,4,5)P3, a lipid second messenger that recruits cytosolic signaling proteins to the plasma membrane and initiates downstream pathways influencing growth and metabolism.

PI3Ks are classified into three classes (I–III) based on structure, substrate preference, and biology. Class I enzymes are most studied in cancer and include catalytic subunits p110α, p110β, p110δ, and p110γ, with regulatory subunits such as p85. Class II and Class III enzymes have distinct roles in membrane trafficking and autophagy.

The most well-characterized activation occurs with Class I PI3Ks downstream of receptor tyrosine kinases and GPCRs. SH2-domain–containing adapters bridge receptors to the p110 subunits, triggering production of PIP3 at the inner leaflet of the plasma membrane. PIP3 serves to recruit PH-domain proteins such as AKT and PDK1, leading to AKT activation and downstream effects on mTOR signaling.

PTEN and SHIP phosphatases counteract PI3K signaling by dephosphorylating PIP3, thereby restricting the pathway. Dysregulation of PI3K signaling is common in cancers and immune disorders, and selective inhibitors targeting specific isoforms are used clinically or under investigation.

Examples of clinically relevant inhibitors include alpelisib (PIK3CA-mutant cancers), idelalisib (PI3Kδ, B-cell diseases), and pan-PI3K inhibitors such as copanlisib and duvelisib. Treatment considerations include metabolic effects, immune modulation, and infection risk.