β-Arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor (original) (raw)

Nature volume 383, pages 447–450 (1996)Cite this article

Abstract

THE ability of a system to regulate its responsiveness in the presence of a continuous stimulus, often termed desensitization, has been extensively characterized for the β2-adrenergic receptor (β2AR). β2AR signalling is rapidly attenuated through receptor phosphorylation and subsequent binding of the protein β-arrestin1,2. Ultimately the receptor undergoes internalization3,4, and although the molecular mechanism is unclear, receptor phosphorylation and β-arrestin binding have been implicated in this process5,6. Here we report that p-arrestin and arrestin-3, but not visual arrestin, promote β2AR internalization and bind with high affinity directly and stoichiometrically to clathrin, the major structural protein of coated pits. Moreover, β-arrestin/arrestin chimaeras that are defective in either β2AR or clathrin binding show a reduced ability to promote β2AR endocytosis. Immunofluorescence microscopy of intact cells indicates an agonist-dependent colocalization of the β2AR and β-arrestin with clathrin. These results show that β-arrestin functions as an adaptor in the receptor-mediated endocytosis pathway, and suggest a general mechanism for regulating the trafficking of G-protein-coupled receptors.

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References

  1. Sterne-Marr, R. & Benovic, J. L. Vitam. Horm. 51, 193–234 (1995).
    Article CAS Google Scholar
  2. Premont, R. T., Inglese, J. & Lefkowitz, R. J. FASEB J. 9, 175–182 (1995).
    Article CAS Google Scholar
  3. Yu, S. S., Lefkowitz, R. J. & Hausdorff, W. P. J. Biol. Chem. 268, 337–341 (1993).
    CAS PubMed Google Scholar
  4. Pippig, S., Andexinger, S. & Lohse, M. J. Mol. Pharmacol. 47, 666–676 (1995).
    CAS PubMed Google Scholar
  5. Ferguson, S. S. G. et al. J. Biol. Chem. 270, 24782–24789 (1995).
    Article CAS Google Scholar
  6. Ferguson, S. S. G. et al. Science 271, 363–365 (1996).
    Article ADS CAS Google Scholar
  7. von Zastrow, M. & Kobilka, B. K. J. Biol. Chem. 269, 18448–18452 (1994).
    CAS PubMed Google Scholar
  8. Sterne-Marr, R. et al. J. Biol. Chem. 268, 15640–15648 (1993).
    CAS PubMed Google Scholar
  9. Schroder, S. & Ungewickell, E. J. Biol. Chem. 266, 7910–7918 (1991).
    CAS PubMed Google Scholar
  10. Peeler, J. S., Donzell, W. C. & Anderson, R. G. W. J. Cell Biol. 120, 47–54 (1993).
    Article CAS Google Scholar
  11. Schmid, S. L. & Rothman, J. E. J. Biol. Chem. 260, 10044–10049 (1985).
    CAS PubMed Google Scholar
  12. Gurevich, V. V. et al. J. Biol. Chem. 270, 720–731 (1995).
    Article CAS Google Scholar
  13. Keen, J. H. Annu. Rev. Biochem. 59, 415–438 (1990).
    Article CAS Google Scholar
  14. Pearse, B. M. F. & Bretscher, M. S. Annu. Rev. Biochem. 50, 85–101 (1981).
    Article CAS Google Scholar
  15. Pearse, B. M. F. EMBO J. 7, 3331–3336 (1988).
    Article CAS Google Scholar
  16. Sorkin, A. & Carpenter, G. Science 261, 612–615 (1993).
    Article ADS CAS Google Scholar
  17. Nesterov, A., Wiley, H. S. & Gill, G. N. Proc. Natl Acad. Sci. USA 92, 8719–8723 (1995).
    Article ADS CAS Google Scholar
  18. Sorkin, A., Mazzotti, M., Sorkin, T., Scotto, L. & Beguinot, L. J. Biol. Chem. 271, 13377–13384 (1996).
    Article CAS Google Scholar
  19. Santini, F. & Keen, J. H. J. Cell Biol. 132, 1025–1036 (1996).
    Article CAS Google Scholar
  20. Freedman, N. J. et al. J. Biol. Chem. 270, 17953–17961 (1995).
    Article CAS Google Scholar
  21. Diviani, D. et al. J. Biol. Chem. 271, 5049–5058 (1996).
    Article CAS Google Scholar
  22. Gurevich, V. V. & Benovic, J. L. J. Biol. Chem. 267, 21919–21923 (1992).
    CAS PubMed Google Scholar
  23. Keen, J. H., Willingham, M. C. & Pastan, I. H. Cell 16, 303–312 (1979).
    Article CAS Google Scholar
  24. Goodman, O. B. & Keen, J. H. J. Biol. Chem. 270, 23768–23773 (1995).
    Article CAS Google Scholar
  25. Shinohara, T. et al. Proc. Natl Acad. Sci. USA 84, 6975–6979 (1987).
    Article ADS CAS Google Scholar
  26. Lohse, M. J., Benovic, J. L., Codina, J., Caron, M. G. & Lefkowitz, R. J. Science 248, 1547–1550 (1990).
    Article ADS CAS Google Scholar
  27. Dua, H. S. et al. Curr. Eye Res. 11 (suppl.), 107–111 (1992).
    Article Google Scholar
  28. Keen, J. H., Willingham, M. C. & Pastan, I. J. Cell Biol. 256, 2538–2544 (1981).
    CAS Google Scholar

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Author notes

  1. Vsevolod V. Gurevich
    Present address: Sun Health Research Institute, Sun City, Arizona, 85372, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Pharmacology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA
    Oscar B. Goodman Jr, Jason G. Krupnick, Francesca Santini, Vsevolod V. Gurevich, Raymond B. Penn, Alison W. Gagnon, James H. Keen & Jeffrey L. Benovic

Authors

  1. Oscar B. Goodman Jr
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  2. Jason G. Krupnick
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  3. Francesca Santini
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  4. Vsevolod V. Gurevich
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  5. Raymond B. Penn
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  6. Alison W. Gagnon
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  7. James H. Keen
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  8. Jeffrey L. Benovic
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Goodman, O., Krupnick, J., Santini, F. et al. β-Arrestin acts as a clathrin adaptor in endocytosis of the β2-adrenergic receptor.Nature 383, 447–450 (1996). https://doi.org/10.1038/383447a0

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