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The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin

Nature volume 422, pages 629–633 (2003)Cite this article

Abstract

Insulin stimulates glucose transport by promoting exocytosis of the glucose transporter Glut4 (refs 1, 2). The dynamic processes involved in the trafficking of Glut4-containing vesicles, and in their targeting, docking and fusion at the plasma membrane, as well as the signalling processes that govern these events, are not well understood. We recently described tyrosine-phosphorylation events restricted to subdomains of the plasma membrane that result in activation of the G protein TC10 (refs 3, 4). Here we show that TC10 interacts with one of the components of the exocyst complex, Exo70. Exo70 translocates to the plasma membrane in response to insulin through the activation of TC10, where it assembles a multiprotein complex that includes Sec6 and Sec8. Overexpression of an Exo70 mutant blocked insulin-stimulated glucose uptake, but not the trafficking of Glut4 to the plasma membrane. However, this mutant did block the extracellular exposure of the Glut4 protein. So, the exocyst might have a crucial role in the targeting of the Glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion.

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Figure 1: Exo70 interacts with activated TC10.
Figure 2: Exo70 is translocated to the plasma membrane by insulin.
Figure 3: Components of the exocyst complex translocate to the plasma membrane in response to insulin.
Figure 4: Exo70 plays a crucial role in Glut4 vesicle targeting.

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References

  1. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Bryant, N. J., Govers, R. & James, D. E. Regulated transport of the glucose transporter GLUT4. Nature Rev. Mol. Cell Biol. 3, 267–277 (2002)

    Article  CAS  Google Scholar 

  3. Chiang, S. H. et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410, 944–948 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Liu, J., Kimura, A., Baumann, C. A. & Saltiel, A. R. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol. Cell. Biol. 22, 3599–3609 (2002)

    Article  CAS  Google Scholar 

  5. Neudauer, C. L., Joberty, G., Tatsis, N. & Macara, I. G. Distinct cellular effects and interactions of the Rho-family GTPase TC10. Curr. Biol. 8, 1151–1160 (1998)

    Article  CAS  Google Scholar 

  6. TerBush, D. R., Maurice, T., Roth, D. & Novick, P. The exocyst is a multiprotein complex required for exocytosis in Saccharomyces cerevisiae. EMBO J. 15, 6483–6494 (1996)

    Article  CAS  Google Scholar 

  7. Kee, Y. et al. Subunit structure of the mammalian exocyst complex. Proc. Natl Acad. Sci. USA 94, 14438–14443 (1997)

    Article  ADS  CAS  Google Scholar 

  8. Symons, M. Rho family GTPases: the cytoskeleton and beyond. Trends Biochem. Sci. 21, 178–181 (1996)

    Article  CAS  Google Scholar 

  9. Tapon, N. & Hall, A. Rho, Rac, and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr. Opin. Cell Biol. 9, 86–92 (1997)

    Article  CAS  Google Scholar 

  10. Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997)

    Article  CAS  Google Scholar 

  11. Chiang, S. H., Hou, J. C., Hwang, J., Pessin, J. E. & Saltiel, A. R. Cloning and functional characterization of related TC10 isoforms, a subfamily of Rho proteins involved in insulin-stimulated glucose transport. J. Biol. Chem. 277, 13067–13073 (2002)

    Article  CAS  Google Scholar 

  12. Hsu, S. C., Hazuka, C. D., Foletti, D. L. & Scheller, R. H. Targeting vesicles to specific sites on the plasma membrane: the role of the sec6/8 complex. Trends Cell. Biol. 9, 150–153 (1999)

    Article  CAS  Google Scholar 

  13. Guo, W., Sacher, M., Barrowman, J., Ferro-Novick, S. & Novick, P. Protein complexes in transport vesicle targeting. Trends Cell Biol. 10, 251–255 (2000)

    Article  CAS  Google Scholar 

  14. Lipschutz, J. H. & Mostov, K. E. Exocytosis: the many masters of the exocyst. Curr. Biol. 12, R212–R214 (2002)

    Article  CAS  Google Scholar 

  15. Ting, A. E. et al. rSec6 and rSec8, mammalian homologs of yeast proteins essential for secretion. Proc. Natl Acad. Sci. USA 92, 9613–9617 (1995)

    Article  ADS  CAS  Google Scholar 

  16. Yeaman, C., Grindstaff, K. K., Wright, J. R. & Nelson, W. J. Sec6/8 complexes on trans-Golgi network and plasma membrane regulate late stages of exocytosis in mammalian cells. J. Cell Biol. 155, 593–604 (2001)

    Article  CAS  Google Scholar 

  17. Kimura, A., Baumann, C. A., Chiang, S. H. & Saltiel, A. R. The sorbin homology domain: a motif for the targeting of proteins to lipid rafts. Proc. Natl Acad. Sci. USA 98, 9098–9103 (2001)

    Article  ADS  CAS  Google Scholar 

  18. Dawson, K., Aviles-Hernandez, A., Cushman, S. W. & Malide, D. Insulin-regulated trafficking of dual-labelled glucose transporter 4 in primary rat adipose cells. Biochem. Biophys. Res. Commun. 287, 445–454 (2001)

    Article  CAS  Google Scholar 

  19. Novick, P. & Guo, W. Ras family therapy: Rab, Rho and Ral talk to the exocyst. Trends Cell Biol. 12, 247–249 (2002)

    Article  CAS  Google Scholar 

  20. Cheatham, B. GLUT4 and company: SNAREing roles in insulin-regulated glucose uptake. Trends Endocrinol. Metab. 11, 356–361 (2000)

    Article  CAS  Google Scholar 

  21. Chamberlain, L. H. & Gould, G. W. The v-and t-SNARE proteins that mediate Glut4 vesicle fusion are localised in detergent-insoluble lipid rafts present on distinct intracellular membranes. J. Biol. Chem. 277, 49750–49754 (2002)

    Article  CAS  Google Scholar 

  22. Sherman, L. A., Hirshman, M. F., Cormont, M., Le Marchand-Brustel, Y. & Goodyear, L. J. Differential effects of insulin and exercise on Rab4 distribution in rat skeletal muscle. Endocrinology 137, 266–273 (1996)

    Article  CAS  Google Scholar 

  23. Cormont, M. et al. Potential role of Rab4 in the regulation of subcellular localization of Glut4 in adipocytes. Mol. Cell. Biol. 16, 6879–6886 (1996)

    Article  CAS  Google Scholar 

  24. Shisheva, A. & Czech, M. P. Association of cytosolic Rab4 with GDI isoforms in insulin-sensitive 3T3-L1 adipocytes. Biochemistry 36, 6564–6570 (1997)

    Article  CAS  Google Scholar 

  25. Millar, C. A., Shewan, A., Hickson, G. R., James, D. E. & Gould, G. W. Differential regulation of secretory compartments containing the insulin-responsive glucose transporter 4 in 3T3-L1 adipocytes. Mol. Biol. Cell 10, 3675–3688 (1999)

    Article  CAS  Google Scholar 

  26. Chang, L., Adams, R. D. & Saltiel, A. R. The TC10-interacting protein CIP4/2 is required for insulin-stimulated Glut4 translocation in 3T3L1 adipocytes. Proc. Natl Acad. Sci. USA 99, 12835–12840 (2002)

    Article  ADS  CAS  Google Scholar 

  27. Lin, D. et al. A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000)

    Article  CAS  Google Scholar 

  28. Thurmond, D. C. et al. Regulation of insulin-stimulated GLUT4 translocation by Munc18c in 3T3L1 adipocytes. J. Biol. Chem. 273, 33876–33883 (1998)

    Article  CAS  Google Scholar 

  29. Hwang, J. B. & Frost, S. C. Effect of alternative glycosylation on insulin receptor processing. J. Biol. Chem. 274, 22813–22820 (1999)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institutes of Health. We thank T-H. Chun for helpful discussions.

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Authors and Affiliations

  1. Life Sciences Institute, Departments of Internal Medicine and Physiology, University of Michigan Medical Center, Ann Arbor, Michigan, 48109, USA

    Mayumi Inoue, Louise Chang, Joseph Hwang, Shian-Huey Chiang & Alan R. Saltiel

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  1. Mayumi Inoue
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  2. Louise Chang
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  3. Joseph Hwang
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  5. Alan R. Saltiel
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Correspondence to Alan R. Saltiel.

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Inoue, M., Chang, L., Hwang, J. et al. The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 422, 629–633 (2003). https://doi.org/10.1038/nature01533

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