Molecular basis for the integration of inositol phosphate signaling pathways via human ITPK1

The synthesis and the metabolism of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P₄) are the responsibility of a single multifunctional kinase/phosphotransferase, ITPK1. This enzyme dynamically couples the cellular levels of Ins(3,4,5,6)P₄ to the receptor-dependent hydrolysis of inositol lipids by phospholipase C. This is a biologically significant event because Ins(3,4,5,6)P₄ regulates the conductance of a specialized class of chloride ion channels, which regulate many cellular functions including epithelial salt and fluid secretion, synaptic efficacy, bone remodelling, tumor cell migration, insulin release from pancreatic β-cells, and inflammatory responses. This review assesses the current state of our knowledge of this versatile and ubiquitous signalling cascade.