The 7 phosphoinositides (PIs) and their metabolism. The PI molecule includes inositol 1-phosphate (a hydrophilic portion exposed to the cytosol) bound via the phosphate group to 1-R1, 2-R2 diacylglycerol (a hydrophobic membrane-anchored portion). Depicted are the major pathways for synthesis and turnover confirmed both in vitro and in vivo (solid arrows). The routes implicated in insulin-regulated glucose transporter 4 (GLUT4) vesicle translocation discussed herein are in gray arrows. R1/R2, fatty acid; P, phosphate; PI3K, PI4K, and PI5K, PI 3-kinase, PI 4-kinase, and PI 5-kinase, respectively; PtdIns 4K, phosphatidylinositol 4-kinase; MTM, myotubularin; MTMR, myotubularin related; IpgD, entry-mediating invasin phosphatase; OCRL, phosphatase implicated in the oculocerebrorenal syndrome of Lowe; PtdIns(3)P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P₂, phosphatidylinositol 3,5-bisphosphate; PtdIns(5)P, phosphatidylinositol 5-phosphate; PtdIns(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PIKfyve, phosphoinositide kinase for position five containing the FYVE domain; SHIP2, Src homology 2 containing inositol 5-phosphatase; SKIP, skeletal muscle- and kidney-enriched inositol phosphatase; PtdIns(3,4,5)P₃, phosphatidylinositol 3,4,5-trisphosphate; PtdIns(4)P, phosphatidylinositol 4-phosphate; PtdIns(3,4)P₂, phosphatidylinositol 3,4-bisphosphate.

Schematic model for the sites of PI's action in insulin-regulated multistep process of GLUT4 translocation in adipose and muscle cells. GLUT4 endocytosis requires PtdIns(4,5)P₂, whose insulin-dependent regulation is uncertain. A subpopulation of GLUT4 exits sorting endosomes/early endosomes (SE/EE) and via recycling endosomes/trans-Golgi network (RE/TGN) enters into GLUT4 storage vesicles (GSVs) in an insulin-regulated process that requires robust endosomal PtdIns(3,5)P₂ synthesis by PIKfyve and its associated regulator ArPIKfyve. A subpopulation of small GLUT4 vesicle intermediates that may also bud off from SE/EE contain PtdIns4K IIα and remain nonresponsive to insulin (NRC). Insulin-dependent movement of GSV requires PI3K-C2α-catalyzed PtdIns(3)P synthesis that may also affect events at the cell surface. GLUT4 movement/tethering requires an insulin-regulated filamentous actin remodeling regulated by robust change in PtdIns(5)P and/or PtdIns(4,5)P₂. Signals mediated by insulin-activated class IA PI3K and PtdIns(3,4,5)P₃ synthesis regulate GLUT4 docking/fusion. The PtdIns(3,4,5)P₃ (red), PtdIns(3)P (yellow), and PtdIns(4,5)P₂ (orange) basal or insulin-regulated localizations at plasma membrane subdomains are confirmed by specific reporters containing selective pleckstrin homology domains [for PtdIns(3,4,5)P₃ and PtdIns(4,5)P₂ binding] or the FYVE finger domain [for PtdIns(3)P binding]. Compartments/microdomains of basal or altered PtdIns(3,5)P₂, PtdIns(5)P, and PtdIns(4)P in response to insulin have not been verified by specific bioreporters. The individual steps in the overall GLUT4 translocation are in italics. See text for more details. N-WASP, neural Wiskott-Aldrich syndrome protein.