PI3Kα

Phosphatidylinositol 3-kinase alpha (PI3Kα) is a lipid kinase that belongs to class IA of the PI3K kinase family together with beta and delta isoforms. Once activated, PI3Kα phosphorylates the phosphatidylinositol 4,5-bisphosphate (PIP2) lipid component on the cell membrane to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 then activates downstream signaling components, such as AKT kinase that is involved in cell growth and survival. Dysregulation of the PI3Kα-mediated signaling pathway is strongly associated with cancerogenesis. PI3Kα is a heterodimer composed of two subunits: catalytic p110α and regulatory p85α unit. The catalytic unit is encoded by the PIK3CA gene that is most frequently mutated in cancer. The hotspot mutations E542K and E545K occur in the helical domain of p110α and disrupt its interactions with the regulatory unit, which disables PI3Kα auto-inhibition. For this reason, PI3Kα is a critical anti-cancer drug target.