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(1,2). As parkin encodes an E3 ubiquitin ligase(3), defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease(4). 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(5). 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(6-8), thereby delaying EGFR internalization and degradation, and promoting PI( 3)K-Akt signalling. Considering the role of Akt in neuronal survival(9), our results have broad new implications for understanding the pathogenesis of Parkinson's disease.