Phosphatidylinositol 4-kinase alpha (PI4KA) (PI4KA)

Phosphatidylinositol 4-kinase alpha (PI4KA) is a type III lipid kinase that catalyzes the phosphorylation of phosphatidylinositol to produce phosphatidylinositol 4-phosphate (PI4P), primarily at the plasma membrane (UniProt P42356). It functions as part of a heterotetrameric complex with EFR3, TTC7, and FAM126, which is essential for maintaining the phosphoinositide pools required for signal transduction and membrane trafficking (PubMed: 23229899). PI4KA is a critical host factor for the replication of the hepatitis C virus (HCV), as it is recruited by the viral protein NS5A to create the "membranous web" necessary for viral assembly (PubMed: 21238945). In oncology, PI4KA is often overexpressed and promotes tumor progression, particularly in hepatocellular and pancreatic cancers, by modulating cytoskeleton organization and survival pathways like PI3K/Akt (PubMed: 37979461). Small molecule inhibitors such as AL-9 and GSK-A1 have been developed to target PI4KA for antiviral and anticancer applications, but their clinical advancement has been hindered by significant safety concerns (PubMed: 24417819). Systemic depletion of PI4P through pharmacological inhibition can lead to lethal gastrointestinal and cardiovascular toxicities, while biallelic loss-of-function mutations in humans cause severe neurodevelopmental and immunological disorders (PubMed: 33151155).

Other names

PI4KIIIaPIK4CAPI4K-ALPHApi4K230PMGYCHASPG84GIDID2hPI4KA

Inhibition of the catalytic activity of PI4KA, leading to depletion of phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-bisphosphate (PIP2) pools at the plasma membrane, which disrupts the formation of the hepatitis C virus (HCV) membranous web and inhibits oncogenic signaling pathways such as KRAS and Akt2.