Nature Cell Biology
- 8, 834 - 842 (2006)
Published online: 23 July 2006; | doi:10.1038/ncb1441
A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signallingLara Fallon1, Catherine M.L. Bélanger1, Amadou T. Corera1, Maria Kontogiannea1, Elsa Regan-Klapisz2, France Moreau1, Jarno Voortman2, Michael Haber1, Geneviève Rouleau1, Thorhildur Thorarinsdottir1, Alexis Brice3, Paul M.P. van Bergen en Henegouwen2 & Edward A. Fon11
Centre for Neuronal Survival and Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4. 2
Molecular Cell Biology, Institute of Biomembranes, Universiteit Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands. 3
INSERM U. 679 and Department of Genetics, Cytogenetics and Embryology, Goupe Hospitalier Pitié-Salpêtrière, 47, Bd de l'Hôpital 75651, Paris Cedex 13, France.
Correspondence should be addressed to Edward A. Fon ted.fon@mcgill.ca ubiquitinepsinUIM1UIM2Mutations 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.
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