Structural insights into Phospholipase Cε activity and regulation

Phospholipase Cε (PLCε) is a complex, multifunctional enzyme that responds to and integrates signals from G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) through the direct binding of G proteins. These activators translocate PLCε to the cytoplasmic leaflets of the plasma and perinuclear membranes where the lipase hydrolyzes phosphatidylinositol (PI) lipids to produce inositol polyphosphates (IPs) and diacylglycerol (DAG). These second messengers increase intracellular Ca 2+ and/or activate protein kinase C, respectively, stimulating numerous pathways. Recent studies have broadened our understanding of this enzyme, revealing roles for PLCε in Ca 2+ -induced Ca 2+ -release (CICR) processes in the kidneys and pancreas, as well as cancer. These are complemented by structural studies that provide more complete insights into its basal and G protein-bound conformations. Here, we summarize and discuss these advances in understanding the regulation and roles of PLCε in normal and pathological contexts.