PI3Ks

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-position of the inositol ring of phosphoinositides. Their activity generates membrane-bound second messengers that regulate growth, metabolism, survival, and vesicle trafficking. PI3Ks are classified into three main classes (I–III) based on substrate preference, regulation, and structure.

Class I PI3Ks are heterodimers with catalytic subunits p110α, p110β, p110δ, or p110γ and regulatory subunits such as p85. They are activated by receptor tyrosine kinases and GPCRs. They phosphorylate PI(4,5)P2 to PI(3,4,5)P3 (PIP3), recruiting PH-domain effectors and activating AKT/mTOR signaling.

Class II PI3Ks (PI3K-C2α, -C2β, -C2γ) are monomeric and generate PI(3)P and PI(3,4)P2; their roles include endocytosis and membrane trafficking. Class III PI3K (Vps34) primarily produces PI(3)P and regulates autophagy and endosomal trafficking. Together, these classes regulate membrane dynamics and intracellular signaling.

PI3K signaling interfaces with many pathways. The production of PIP3 promotes recruitment of PH-domain proteins such as AKT and PDK1, triggering phosphorylation cascades that control cell growth, survival, metabolism, and cytoskeletal organization. Dysregulation of PI3K activity is linked to cancer, immune disorders, and metabolic disease.

Therapeutically, PI3Ks are targets in oncology and immunology. Oncogenic mutations in PIK3CA or loss of PTEN increase signaling. Isoform-selective inhibitors such as alpelisib (p110α) and idelalisib (p110δ), as well as dual or pan-PI3K inhibitors, are approved for various cancers; adverse effects include hyperglycemia and rash.