Abstract
Phosphoinositides are membrane-localized phospholipids that regulate a plethora of essential cellular processes. These lipid signaling molecules are critical for cell homeostasis and therefore their levels are strictly regulated by the coordinated action of several families of lipid kinases and phosphatases. In this review, we provide a focused perspective on the phosphatidylinositol phosphate kinase (PIPK) family and the three subfamilies that compose it: Type I PIPKs or phosphatidylinositol-4-phosphate 5-kinases (PI4P5Ks), Type II PIPKs or phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks), and Type III PIPKs or phosphatidylinositol-3-phosphate 5-kinases (PIKfyve). Each subfamily is responsible for catalyzing a hydroxyl phosphorylation on specific phosphoinositide species to generate a double phosphorylated lipid, therefore regulating the levels of both substrate and product. Here, we summarize our current knowledge about the functions and regulation of each PIPK subfamily. Further, we highlight the roles of these kinases in various in vivo genetic models and give an overview of their involvement in multiple pathological conditions. The phosphoinositide field has been long focused on targeting PI3K signaling, but growing evidence suggests that it is time to draw attention to the other phosphoinositide kinases. The discovery of the involvement of PIPKs in the pathogenesis of multiple diseases has prompted substantial efforts to turn these enzymes into pharmacological targets. An increasingly refined knowledge of the biology of PIPKs in a variety of in vitro and in vivo models will facilitate the development of effective approaches for therapeutic intervention with the potential to translate into meaningful clinical benefits for patients suffering from cancer, immunological and infectious diseases, and neurodegenerative disorders.