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

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.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…EPS15 also associates with the clathrin adaptor protein AP-2 on receptor activation and may bind ubiquitinated EGFR through ubiquitin-interacting motifs (UIMs) to promote receptor endocytosis [90]. Parkin, an E3 ubiquitin ligase, promotes signaling through the PI(3)K/Akt pathway by activated EGFR by binding the UIM of EPS15 and limiting receptor endocytosis [91]. Surprisingly, endocytosis does not require activation of the EGFR tyrosine kinase domain, and rather appears dependent on receptor dimerization [84,85].…”

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

“…As illustrated below, nitrosative/oxidative stress, commonly found during normal aging, can mimic rare genetic causes of disorders, such as PD, by promoting protein misfolding in the absence of a genetic mutation. 17,18,20 Recently, Fallon et al 67 reported that the protein parkin can mediate neuronal survival via a proteasome-independent pathway. In this model, parkin monoubiquitinates the epidermal growth factor receptor (EGFR)-associated protein, Eps15, leading to inhibition of EGFR endocytosis.…”

“…Downregulation of parkin may also result in a decrease in the neuroprotective activity of Akt because of enhanced EGFR internalization and thus less Akt signaling. 67 DA quinone can also modify the cysteine thiols of parkin and reduce its activity. 72 Ub: ubiquitin this reaction inhibits both its isomerase and chaperone activities.…”

Protein monoubiquitylation: targets and diverse functions

“…Two E3 ligases, NEDD4 and Parkin, have been implicated in the monoubiquitylation of EPS15 (Fallon et al . 2006; Woelk et al . 2006).…”

“…Another mechanism by which Parkin inhibits apoptosis was shown by the finding that Parkin monoubiquitylates and thereby inactivates the endocytic adaptor protein EPS15 (Fallon et al . 2006). EPS15 is an important regulator of growth factor receptor internalization, as described above, and its inactivation by Parkin therefore enhances survival signaling emanating from cell surface receptors—enhancement that is compromised by Parkin mutations.…”