A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling.
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.
Fallon
Lara
L
Centre for Neuronal Survival and Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
Bélanger
Catherine M L
CM
Corera
Amadou T
AT
Kontogiannea
Maria
M
Regan-Klapisz
Elsa
E
Moreau
France
F
Voortman
Jarno
J
Haber
Michael
M
Rouleau
Geneviève
G
Thorarinsdottir
Thorhildur
T
Brice
Alexis
A
van Bergen En Henegouwen
Paul M P
PM
Fon
Edward A
EA
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D044767:Ubiquitin-Protein Ligases; C486204:EPN2 protein, human; C111567:parkin protein