A Role for Parkin in Regulating EGFR Endocytosis

Abstract

Ubiquitination is a posttranslational modification most familiar for its role in targeting proteins for proteasomal degradation. However, Fallon et al. discovered that the ubiquitin-like domain (Ubl) of parkin [an E3 ubiquitin ligase, mutation of which has been implicated in a familial form of Parkinson's disease (PD)] failed to interact with ubiquitin-interacting motifs (UIMs) within the proteasomal S5a subunit, leading them to search for other ubiquitin-dependent roles for parkin. Pulldown assays revealed both Ubl-UIM-mediated and Ubl-independent interactions between parkin and Eps15, an adaptor protein involved in endocytosis of the epidermal growth factor (EGF) receptor (EGFR). EGF treatment of Her14 cells transiently increased association of parkin with Eps15 as well as association of parkin and Eps15 with EGFR. EGF stimulates Eps15 ubiquitination, and this was enhanced by expression of wild-type parkin (which ubiquitinated Eps15 in vitro) but not by two mutant forms associated with PD. Experiments involving parkin overexpression or loss in cell lines indicated that parkin slowed EGFR endocytosis; moreover, lack of parkin was associated with a decrease in EGF-stimulated Akt phosphorylation in both HeLa cells and mouse brain synaptosomes. The effects of parkin on EGFR endocytosis and Akt signaling both depended on the presence of Eps15. Noting that EGFR signaling protects dopaminergic neurons in models of PD, the authors suggest that the loss of parkin-dependent regulation of EGFR endocytosis and Akt signaling (mediated through its ubiquitination of Eps15) may contribute to the pathogenesis of PD. Husnjak and Dikic discuss the research in a News and Views article. L. Fallon, C. M. L. Belanger, A. T. Corera, M. Kontogiannea, E. Regan-Klapisz, F. Moreau, J. Voortman, M. Haber, G. Rouleau, T. Thorarinsdottir, A. Brice, P. M. P. van Bergen en Henegouwen, E. A. Fon, 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). [PubMed] K. Husnjak, I. Dikic, EGFR trafficking: Parkin' in a jam. Nat. Cell Biol. 8 , 787-788 (2006). [PubMed]