Phosphoinositides in insulin action on GLUT4 dynamics: not just PtdIns(3,4,5)P3

Abstract

Accumulated evidence over the last several years indicates that insulin regulates multiple steps in the overall translocation of GLUT4 vesicles to the fat/muscle cell surface, including formation of an intracellular storage pool of GLUT4 vesicles, its movement to the proximity of the cell surface, and the subsequent docking/fusion with the plasma membrane. Insulin-stimulated formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3); and in some cases, of its catabolite PtdIns(3,4)P(2)] plays a pivotal role in this process. PtdIns(3,4,5)P(3) is synthesized by the activated wortmannin-sensitive class IA phosphoinositide (PI) 3-kinase and controls the rate-limiting cell surface terminal stages of the GLUT4 journey. However, recent research is consistent with the conclusion that signals by each of the remaining five PIs, i.e., PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P(2), and PtdIns(4,5)P(2), may act in concert with that of PtdIns(3,4,5)P(3) in integrating the insulin receptor-issued signals with GLUT4 surface translocation and glucose transport activation. This review summarizes the experimental evidence supporting the complementary function of these PIs in insulin responsiveness of fat and muscle cells, with particular reference to mechanistic insights and functional significance in the regulation of overall GLUT4 vesicle dynamics.

Fig. 1.

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.

Fig. 2.

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.