PI3KA

PI3KA refers to the catalytic subunit of class IA phosphoinositide 3-kinases, most commonly the p110α subunit encoded by the PIK3CA gene. The enzyme phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), a second messenger that activates downstream signaling through AKT and other effectors, thereby influencing cell growth, survival, metabolism, and proliferation.

In cells, PI3KA forms heterodimers with regulatory subunits of the p85 family (such as p85α, p85β) and other regulatory proteins. Activation of class IA PI3Ks is typically initiated by receptor tyrosine kinases, which recruit the p85 subunit to phosphotyrosine motifs. This relieves inhibitory interactions and localizes the catalytic subunit to the plasma membrane where it can access its lipid substrate. Negative regulation is provided by phosphatases such as PTEN and SHIP, which dephosphorylate PIP3.

Biological and clinical significance of PI3KA includes its essential role in normal development and physiology, as well as disease when the pathway becomes dysregulated. Somatic mutations in PIK3CA are among the most frequent alterations in human cancers and can lead to constitutive activation of the PI3K-AKT pathway. Typical hotspot mutations occur in the helical (for example E542K, E545K) and kinase (such as H1047R) domains. In addition to cancer, PIK3CA mutations are associated with a spectrum of overgrowth conditions.

Therapeutically, selective inhibitors targeting PI3Kα, such as alpelisib, have been developed and approved for certain PIK3CA-mutant cancers, notably hormone receptor–positive, HER2-negative breast cancer. Side effects can include hyperglycemia, rash, and fatigue, reflecting the pathway’s role in normal metabolic and immune processes.