PI5K

PI5K, short for phosphatidylinositol-5-kinase, is a family of lipid kinases that phosphorylate the 5-position of the inositol ring of phosphatidylinositol 4-phosphate to generate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). In humans, the PI5K family is divided into two subfamilies: type I PIP5Ks (PIP5K1A, PIP5K1B, PIP5K1C) and type II PIP5Ks (PIP5K2A, PIP5K2B). All members share a catalytic kinase domain and regulate distinct pools of PI(4,5)P2 at various membranes, including the plasma membrane, Golgi, and endosomes.

Functionally, PI(4,5)P2 is a central signaling lipid that acts as a substrate for phospholipase C to generate second messengers and serves as a docking site for multiple effector proteins with lipid-binding domains. Consequently, PI5Ks influence actin cytoskeleton remodeling, vesicular trafficking, endocytosis and exocytosis, and membrane curvature.

Regulation is complex and context-dependent. PI5K activity is modulated by small GTPases (such as members of the Rho and Arf families), protein–protein interactions, phosphorylation, and membrane composition. Isoforms display distinct cellular localizations and regulatory controls, enabling fine-tuned generation of PI(4,5)P2 pools.

Clinical relevance: Altered PI(4,5)P2 production by PI5Ks has been linked to cancer cell migration and invasion, metabolic signaling, and neurological processes. Animal and cellular models reveal essential roles for PI5Ks in development and homeostasis.

Research and tools: Genetic ablation and pharmacological inhibition of PI5Ks are used to study PI(4,5)P2 signaling, though selectivity remains a challenge and no PI5K-targeted therapies are approved.