Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signalling

Nature Cell Biology volume 8, pages 834–842 (2006)Cite this article

Abstract

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease1,2. As parkin encodes an E3 ubiquitin ligase3, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease4. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking5. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)–Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR6,7,8, thereby delaying EGFR internalization and degradation, and promoting PI(3)K–Akt signalling. Considering the role of Akt in neuronal survival9, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Parkin binds Eps15 via a Ubl–UIM interaction.
Figure 2: EGF regulates the interaction between parkin, Eps15 and the EGFR, and stimulates parkin-mediated Eps15 ubiquitination.
Figure 3: Regulation of parkin activity and Eps15 binding.
Figure 4: Parkin regulates EGFR endocytosis.
Figure 5: Parkin regulates EGFR degradation and signalling via the PI(3)K–Akt pathway.

Similar content being viewed by others

References

  1. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  Google Scholar 

  2. Lucking, C. B. et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group. N. Engl. J. Med. 342, 1560–1567 (2000).

    Article  CAS  Google Scholar 

  3. Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet. 25, 302–305 (2000).

    Article  CAS  Google Scholar 

  4. Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57–87 (2005).

    Article  CAS  Google Scholar 

  5. Confalonieri, S., Salcini, A. E., Puri, C., Tacchetti, C. & Di Fiore, P. P. Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis. J. Cell Biol. 150, 905–912 (2000).

    Article  CAS  Google Scholar 

  6. Sigismund, S. et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc. Natl Acad. Sci. USA 102, 2760–2765 (2005).

    Article  CAS  Google Scholar 

  7. de Melker, A. A., van der Horst, G. & Borst, J. c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15. J. Cell Sci. 117, 5001–5012 (2004).

    Article  CAS  Google Scholar 

  8. Hoeller, D. et al. Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biol. 8, 163–169 (2006).

    Article  CAS  Google Scholar 

  9. Brunet, A., Datta, S. R. & Greenberg, M. E. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297–305 (2001).

    Article  CAS  Google Scholar 

  10. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  Google Scholar 

  11. Goldberg, M. S. et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278, 43628–43635 (2003).

    Article  CAS  Google Scholar 

  12. Ko, H. S. et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J. Neurosci. 25, 7968–7978 (2005).

    Article  CAS  Google Scholar 

  13. Periquet, M., Corti, O., Jacquier, S. & Brice, A. Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J. Neurochem. 95, 1259–1276 (2005).

    Article  CAS  Google Scholar 

  14. Young, P., Deveraux, Q., Beal, R. E., Pickart, C. M. & Rechsteiner, M. Characterization of two polyubiquitin binding sites in the 26 S protease subunit 5a. J. Biol. Chem. 273, 5461–5467 (1998).

    Article  CAS  Google Scholar 

  15. Walters, K. J., Kleijnen, M. F., Goh, A. M., Wagner, G. & Howley, P. M. Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a. Biochemistry 41, 1767–1777 (2002).

    Article  CAS  Google Scholar 

  16. Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell. Dev. Biol. 19, 141–172 (2003).

    Article  CAS  Google Scholar 

  17. Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).

    Article  CAS  Google Scholar 

  18. Klapisz, E. et al. A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination. J. Biol. Chem. 277, 30746–30753 (2002).

    Article  CAS  Google Scholar 

  19. Di Fiore, P. P., Polo, S. & Hofmann, K. When ubiquitin meets ubiquitin receptors: a signalling connection. Nature Rev. Mol. Cell. Biol. 4, 491–497 (2003).

    Article  CAS  Google Scholar 

  20. Fazioli, F., Minichiello, L., Matoskova, B., Wong, W. T. & Di Fiore, P. P. eps15, a novel tyrosine kinase substrate, exhibits transforming activity. Mol. Cell. Biol. 13, 5814–5828 (1993).

    Article  CAS  Google Scholar 

  21. van Delft, S., Govers, R., Strous, G. J., Verkleij, A. J. & van Bergen en Henegouwen, P. M. Epidermal growth factor induces ubiquitination of Eps15. J. Biol. Chem. 272, 14013–14016 (1997).

    Article  CAS  Google Scholar 

  22. Cesari, R. et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc. Natl Acad. Sci. USA 100, 5956–5961 (2003).

    Article  CAS  Google Scholar 

  23. Denison, S. R. et al. Alterations in the common fragile site gene Parkin in ovarian and other cancers. Oncogene 22, 8370–8378 (2003).

    Article  CAS  Google Scholar 

  24. Pawlyk, A. C. et al. Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J. Biol. Chem. 278, 48120–48128 (2003).

    Article  CAS  Google Scholar 

  25. Huang, F., Khvorova, A., Marshall, W. & Sorkin, A. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J. Biol. Chem. 279, 16657–16661 (2004).

    Article  CAS  Google Scholar 

  26. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell. Biol. 3, 893–905 (2002).

    Article  CAS  Google Scholar 

  27. Torrisi, M. R. et al. Eps15 is recruited to the plasma membrane upon epidermal growth factor receptor activation and localizes to components of the endocytic pathway during receptor internalization. Mol. Biol. Cell 10, 417–434 (1999).

    Article  CAS  Google Scholar 

  28. Faundez, V., Krauss, R., Holuigue, L., Garrido, J. & Gonzalez, A. Epidermal growth factor receptor in synaptic fractions of the rat central nervous system. J. Biol. Chem. 267, 20363–20370 (1992).

    CAS  PubMed  Google Scholar 

  29. Fallon, L. et al. Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J. Biol. Chem. 277, 486–491 (2002).

    Article  CAS  Google Scholar 

  30. Koprivica, V. et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310, 106–110 (2005).

    Article  CAS  Google Scholar 

  31. Iwakura, Y. et al. Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons. J. Neurochem. 93, 974–983 (2005).

    Article  CAS  Google Scholar 

  32. Kim, R. H. et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005).

    Article  CAS  Google Scholar 

  33. Yang, Y. et al. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc. Natl Acad. Sci. USA 102, 13670–13675 (2005).

    Article  CAS  Google Scholar 

  34. Lim, K. L. et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J. Neurosci. 25, 2002–2009 (2005).

    Article  CAS  Google Scholar 

  35. Hicks, A. A. et al. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann. Neurol. 52, 549–555 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. McPherson, W. Sossin, P. Barker and F. Luton for valuable advice and critical reading of the manuscript. We thank P. MacDonald for help with the statistical analysis. This work was supported by the Michael J. Fox Foundation For Parkinson's Research and the Canadian Institutes for Health Research (CIHR). E.A.F. is a CIHR Clinician Scientist.

Author information

Authors and Affiliations

  1. Centre for Neuronal Survival and Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, Quebec, Canada

    Lara Fallon, Catherine M.L. Bélanger, Amadou T. Corera, Maria Kontogiannea, France Moreau, Michael Haber, Geneviève Rouleau, Thorhildur Thorarinsdottir & Edward A. Fon

  2. Molecular Cell Biology, Institute of Biomembranes, Universiteit Utrecht, Padualaan 8, Utrecht, 3584 CH, The Netherlands

    Elsa Regan-Klapisz, Jarno Voortman & Paul M.P. van Bergen en Henegouwen

  3. INSERM U. 679 and Department of Genetics, Cytogenetics and Embryology, Goupe Hospitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital, Paris, 75651, Cedex 13, France

    Alexis Brice

Authors
  1. Lara Fallon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine M.L. Bélanger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amadou T. Corera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Kontogiannea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elsa Regan-Klapisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. France Moreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jarno Voortman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Geneviève Rouleau
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thorhildur Thorarinsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alexis Brice
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Paul M.P. van Bergen en Henegouwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Edward A. Fon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward A. Fon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplemnetary Figure S1, S2, S3, S4 and S5 (PDF 626 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fallon, L., Bélanger, C., Corera, A. et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signalling. Nat Cell Biol 8, 834–842 (2006). https://doi.org/10.1038/ncb1441

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1441

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing