title: Sorbitol activates atypical protein kinase C and GLUT4 glucose transporter translocation/glucose transport through proline-rich tyrosine kinase-2, the extracellular signal-regulated kinase pathway and phospholipase D.
abstract: Sorbitol, "osmotic stress", stimulates GLUT4 glucose transporter translocation to the plasma membrane and glucose transport by a phosphatidylinositol (PI) 3-kinase-independent mechanism that reportedly involves non-receptor proline-rich tyrosine kinase-2 (PYK2) but subsequent events are obscure. In the present study, we found that extracellular signal-regulated kinase (ERK) pathway components, growth-factor-receptor-bound-2 protein, son of sevenless (SOS), RAS, RAF and mitogen-activated protein (MAP) kinase/ERK kinase, MEK(-1), operating downstream of PYK2, were required for sorbitol-stimulated GLUT4 translocation/glucose transport in rat adipocytes, L6 myotubes and 3T3/L1 adipocytes. Furthermore, sorbitol activated atypical protein kinase C (aPKC) through a similar mechanism depending on the PYK2/ERK pathway, independent of PI 3-kinase and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Like PYK2/ERK pathway components, aPKCs were required for sorbitol-stimulated GLUT4 translocation/glucose transport. Interestingly, sorbitol stimulated increases in phospholipase D (PLD) activity and generation of phosphatidic acid (PA), which directly activated aPKCs. As with aPKCs and glucose transport, sorbitol-stimulated PLD activity was dependent on the ERK pathway. Moreover, PLD-generated PA was required for sorbitol-induced activation of aPKCs and GLUT4 translocation/glucose transport. Our findings suggest that sorbitol sequentially activates PYK2, the ERK pathway and PLD, thereby increasing PA, which activates aPKCs and GLUT4 translocation. This mechanism contrasts with that of insulin, which primarily uses PI 3-kinase, D3-PO(4) polyphosphoinositides and PDK-1 to activate aPKCs.
authors.affiliation: J.A. Haley Veterans' Hospital Research Service and Department of Internal Medicine, University of South Florida College of Medicine, 13000 Bruce B. Downs Blvd., Tampa, FL 33612, U.S.A.
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kanoh
authors.forename: Mary L
authors.initials: ML
authors.lastname: Standaert
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.forename: Brent C
authors.initials: BC
authors.lastname: Reed
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004822:Epididymis; D005419:Flavonoids / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D051275:Glucose Transporter Type 4; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology*; D014162:Transfection; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011994:Recombinant Proteins; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat; D013012:Sorbitol; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; C496054:Ptk2b protein, rat; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010739:Phospholipase D; D003620:Dantrolene; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin