title: Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP).
abstract: The glucose transporter 4 (GLUT4) is responsible for glucose uptake in the skeletal muscle. Insulin-induced translocation of GLUT4 to the plasma membrane requires phosphatidylinositol 3-kinase activation-mediated generation of phosphatidylinositol 3,4,5-trisphosphate PIP(3) and subsequent activation of Akt. Previous studies suggested that skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) has negative effects on the regulation of insulin signaling in the skeletal muscle cells. Here, we compared its effects on insulin signaling by selective inhibition of SKIP, SHIP2, and phosphatase and tensin homologue on chromosome 10 (PTEN) by short interfering RNA in the C2C12 myoblast cells. Suppression of SKIP significantly increased the insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate levels and Akt phosphorylation. Furthermore, silencing of SKIP, but not of PTEN, increased the insulin-dependent recruitment of GLUT4 vesicles to the plasma membrane. Taken together, these results imply that SKIP negatively regulates insulin signaling and glucose uptake by inhibiting GLUT4 docking and/or fusion to the plasma membrane.
authors.affiliation: Department of Lipid Biochemistry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ijuin
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; C531212:Pps protein, mouse; C096024:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C487216:Pten protein, rat; C000606435:Inppl1 protein, mouse; C000606436:Inppl1 protein, rat; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases