The multifaceted phosphatidylinositol 5 phosphate 4-kinase proteins: molecular properties and biological functions

Phosphoinositides are regulators of key cell biological processes such as plasma membrane function, vesicular transport, cytoskeletal and nuclear organization. In turn, their levels are tightly controlled by the function of lipid kinases and phosphatases that modify specific hydroxyl groups on the inositol ring. Phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is one such lipid kinase. Although initially discovered as an enzyme that phosphorylates the 4th hydroxyl on the inositol ring of phosphatidylinositol 5 phosphate (PI5P) with exquisite specificity, it has recently emerged that PIP4K may also work on other substrates. Interestingly, recent studies have also proposed functions for this enzyme that do not require its catalytic activity. Although most elements of phosphoinositide signalling are conserved across all eukaryota, a limited number of phosphoinositide kinases and phosphatases including PIP4K seem to be a unique feature of the genomes of organisms that exist in a multicellular state but not unicellular eukaryotes. Genetic studies in model organisms implicate PIP4K function in key processes such as hormone regulated metabolic control as well as cell division and growth. Consequently, PIP4K function has important biomedical implications in the context of cancer, metabolic syndrome and autoimmune disorders. In this review, we analyze emerging findings on PIP4K function and reflect on the biochemical raison d'être of how this protein regulates cell physiology in metazoans.