Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4)

Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4/VPS15) is a large regulatory subunit of the Class III PI3K complex. It acts as a molecular scaffold that coordinates the localization and activation of VPS34 (the catalytic lipid kinase) to produce phosphatidylinositol 3-phosphate (PI3P) on cellular membranes. PI3P generation is essential for autophagy initiation, endosome maturation, and vesicular trafficking. Unique among kinases, its pseudokinase domain binds GTP and is regulated through N-myristoylation, controlling complex assembly and activity. Dysfunction or genetic mutations in PIK3R4/VPS15 are implicated in neurodegenerative conditions, and dysregulation of autophagy pathways in cancer and other diseases highlights its importance as a therapeutic target.

Other names

PI3-kinase regulatory subunit 4VPS15PI3-kinase p150 subunitPhosphoinositide 3-kinase adaptor proteinPhosphatidylinositol 3-kinase-associated p150

Drugs targeting VPS34-PIK3R4 complexes usually act by inhibiting kinase activity (autophagy inhibition), stabilizing complex conformations, or modulating association with membranes to control PI3P production. GTP-binding and myristoylation of the pseudokinase domain are critical regulatory mechanisms.