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-P-3 and PtdIns 3,4-P-2, 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.