USP9X Controls EGFR Fate by Deubiquitinating the Endocytic Adaptor Eps15 - PubMed (original) (raw)
. 2016 Jan 25;26(2):173-183.
doi: 10.1016/j.cub.2015.11.050. Epub 2015 Dec 31.
Affiliations
- PMID: 26748853
- DOI: 10.1016/j.cub.2015.11.050
Free article
USP9X Controls EGFR Fate by Deubiquitinating the Endocytic Adaptor Eps15
Michol Giovanna Savio et al. Curr Biol. 2016.
Free article
Erratum in
- USP9X Controls EGFR Fate by Deubiquitinating the Endocytic Adaptor Eps15.
Savio MG, Wollscheid N, Cavallaro E, Algisi V, Di Fiore PP, Sigismund S, Maspero E, Polo S. Savio MG, et al. Curr Biol. 2023 Dec 18;33(24):5533. doi: 10.1016/j.cub.2023.11.060. Curr Biol. 2023. PMID: 38113830 No abstract available.
Abstract
Following activation by its cognate ligand(s), the epidermal growth factor receptor (EGFR) is rapidly routed to the lysosome for degradation in a ubiquitination-dependent fashion. This pathway represents the major mechanism of long-term attenuation of EGFR signaling, and its deregulation is a significant feature in different types of cancers. Here we demonstrate, through a systematic RNAi-based approach, that several deubiquitinating (DUB) enzymes extend or decrease EGFR half-life upon EGF stimulation. We focus on USP9X, whose depletion severely affects EGFR turnover, interfering with its internalization and trafficking. We identify the endocytic protein Eps15 as one of the critical substrates of USP9X, and we map the Eps15 ubiquitination sites. We found that Eps15 monoubiquitination occurs already at minimal dose of EGF stimulation and is essential for EGFR internalization. Overall, our findings identify USP9X as a novel regulator of EGFR endocytosis and suggest a model whereby cycles of ubiquitination and deubiquitination events on endocytic accessory proteins may regulate the internalization and trafficking of the EGFR toward the lysosomes.
Keywords: EGFR; Eps15; USP9X; deubiquitinating enzymes; ubiquitin.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Comment in
- Integration of cellular ubiquitin and membrane traffic systems: focus on deubiquitylases.
Clague MJ, Urbé S. Clague MJ, et al. FEBS J. 2017 Jun;284(12):1753-1766. doi: 10.1111/febs.14007. Epub 2017 Jan 29. FEBS J. 2017. PMID: 28064438 Free PMC article.
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