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First published online 5 October 2004
doi: 10.1242/jcs.01421

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Insulin but not PDGF relies on actin remodeling and on VAMP2 for GLUT4 translocation in myoblasts

Dòra Török^1,*, Nish Patel^1,2,*, Lellean JeBailey^1,3, Farah S. L. Thong¹, Varinder K. Randhawa^1,3, Amira Klip^1,2,3, and Assaf Rudich^1,

¹ Programme in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada
² Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
³ Department of Biochemistry, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada

Author for correspondence (e-mail: amira{at}sickkids.ca)

Accepted 28 July 2004

Insulin promotes the translocation of glucose transporter 4 (GLUT4) from intracellular pools to the surface of muscle and fat cells via a mechanism dependent on phosphatidylinositol (PtdIns) 3-kinase, actin cytoskeletal remodeling and the v-SNARE VAMP2. The growth factor PDGF-BB also robustly activates PtdIns 3-kinase and induces actin remodeling, raising the question of whether it uses similar mechanisms to insulin in mobilizing GLUT4. In L6 myoblasts stably expressing Myc-tagged GLUT4, neither stimulus affected the rate of GLUT4 endocytosis, confirming that they act primarily by enhancing exocytosis to increase GLUT4 at the cell surface. Although surface GLUT4myc in response to insulin peaked at 10 minutes and remained steady for 30 minutes, PDGF action was transient, peaking at 5 minutes and disappearing by 20 minutes. These GLUT4myc translocation time courses mirrored that of phosphorylation of Akt by the two stimuli. Interestingly, insulin and PDGF caused distinct manifestations of actin remodeling. Insulin induced discrete, long (>5 µm) dorsal actin structures at the cell periphery, whereas PDGF induced multiple short (<5 µm) dorsal structures throughout the cell, including above the nucleus. Latrunculin B, cytochalasin D and jasplakinolide, which disrupt actin dynamics, prevented insulin- and PDGF-induced actin remodeling but significantly inhibited GLUT4myc translocation only in response to insulin (75-85%, P<0.05), not to PDGF (20-30% inhibition). Moreover, transfection of tetanus toxin light chain, which cleaves the v-SNAREs VAMP2 and VAMP3, reduced insulin-induced GLUT4myc translocation by >70% but did not affect the PDGF response. These results suggest that insulin and PDGF rely differently on the actin cytoskeleton and on tetanus-toxin-sensitive VAMPs for mobilizing GLUT4.

Key words: Insulin, PDGF, Actin, VAMP2, GLUT4

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