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

Fallon, Lara, Bélanger, Catherine M.L., Corera, Amadou T., Kontogiannea, Maria, Regan-Klapisz, Elsa, Moreau, France, Voortman, Jarno, Haber, Michael, Rouleau, Geneviève, Thorarinsdottir, Thorhildur, Brice, Alexis, van Bergen en Henegouwen, Paul M.P., Fon, Edward A.·2006·Nature Cell Biology
DOI 10.1038/ncb1441
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Abstract

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. 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 trafficking. 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 EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

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Crossref · 10.1038/ncb1441

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  • These findings do not preclude a role for the ubiquitination of parkin or parkin substrates via other linkages in distinct cellular pathways such as NF-jB signaling, endocytosis and trafficking, and autophagy.

    “These findings do not preclude a role for the ubiquitination of parkin or parkin substrates via other linkages in distinct cellular pathways such as NF-jB signaling (K63, N-terminal/linear)”

    From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Fallon et al, 2006

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Research works printed but not linked: 33

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Metadata

Authors
Fallon, L., Bélanger, C. M. L., Corera, A. T., Kontogiannea, M., Regan-Klapisz, E., Moreau, F., Voortman, J., Haber, M., Rouleau, G., Thorarinsdottir, T., Brice, A., van Bergen en Henegouwen, P. M. P., & Fon, E. A.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2006-07-23
Volume
8
Issue
8
Pages
834-842
ISSN
  • 1465-7392
  • 1476-4679
DOI
10.1038/ncb1441
Cited by
317
References
2
Language
en
Licence
www.springer.com/tdm (tdm)

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