Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases

Phosphorylated derivatives of phosphatydylinositol (PtdIns), collectively called phosphoinositides (PIs), have been recognized as versatile second messengers and modulators of lipid membrane composition in all eukaryotes. Over the last several years, PIs emerged as key membrane-localized signals for regulating a myriad of cellular processes, including insulin-induced membrane receptor signaling, GLUT4 membrane trafficking and the accompanying actin cytoskeletal rearrangement. PIs are synthesized from PtdIns by the action of kinases, specific for one of the 3 hydroxyls at positions D-3, D-4 and D-5 in the inositol head group and are degraded/turned over by the also position-specific action of phosphoinositide phosphatases. Work over the last several years has clearly implicated the products of PI 3-kinase activity, PtdIns 3,4,5-P3 and PtdIns 3,4-P2, as key elements in the proximal insulin receptor signaling circuit that regulates GLUT4 membrane dynamics. Emerging evidence has accumulated to suggest the role for the products of PI 4-kinases and PI 5-kinases in this process, likely at more distal steps. Here I review our current understanding of the role for PIs and the enzymes involved in their turnover in the regulation of GLUT4 membrane dynamics in response to insulin, endothelin-1 and hyperosmotic shock.