Phosphoinositide phosphatases: Modifiers of phosphoinositide signaling in health and disease

Phosphoinositides are membrane-bound phospholipids that are derived from the reversible phosphorylation of phosphatidylinositol by the opposing actions of phosphoinositide kinases and phosphatases. Phosphoinositides are minor lipid constituents of cellular membranes; however, they assert a varied and profound influence on numerous biological processes both at the plasma membrane and on subcellular organelle membranes. Phosphoinositide phosphatases encompass multiple enzyme families that hydrolyze the phosphate group from the inositol ring of phosphoinositide species to modify signaling pathways that govern development and homeostasis. Genetic mutations that alter the function or expression of phosphoinositide phosphatases are causative of severe developmental syndromes or contribute to human diseases such as cancer, metabolic disorders and neuropathies. This review will focus on a select group of phosphoinositide phosphatase family members. Specifically, we will discuss the lipid and dual-specificity protein phosphatase PTEN, including the multiple regulatory mechanisms that define this enzyme as an established tumor suppressor. We will focus on recent discoveries that describe novel roles for phosphoinositide regulation on subcellular membranes by INPP5E and INPP5K, two members of the inositol polyphosphate 5-phosphatase family. Finally, the diverse biological and pathophysiological roles of the inositol polyphosphate 4-phosphatases, INPP4A and INPP4B, will be outlined. Collectively, these discussions will reveal the critical roles that phosphoinositide phosphatases play in both human development and for prevention of disease.