Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity

• Published in: Molecular and cellular biology Vol. 37; no. 9
• Main Authors: Mathien, Simon, Déléris, Paul, Soulez, Mathilde, Voisin, Laure, Meloche, Sylvain
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.05.2017; American Society for Microbiology
• Subjects: bioactive properties; Cell Adhesion - physiology; Cell Line, Tumor; cell movement; Cell Movement - physiology; deubiquitinating enzymes; Deubiquitinating Enzymes - genetics; Deubiquitinating Enzymes - metabolism; ERK3; HEK293 Cells; HeLa Cells; HT29 Cells; Humans; loss-of-function mutation; MAPKs; MCF-7 Cells; microfilaments; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 6 - metabolism; Phosphorylation; proteinases; RNA Interference; RNA, Small Interfering - genetics; Spotlight; Ubiquitin - metabolism; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; ubiquitination; Ubiquitination - physiology; ERK3; deubiquitinating enzymes; MAPKs
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00432-16

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose regulatory mechanisms and biological functions remain superficially understood. Contrary to most protein kinases, ERK3 is a highly unstable protein that is subject to dynamic regulation by the ubiquitin-proteasome system. However, the effectors that control ERK3 ubiquitination and degradation are unknown. In this study, we carried out an unbiased functional loss-of-function screen of the human deubiquitinating enzyme (DUB) family and identified ubiquitin-specific protease 20 (USP20) as a novel ERK3 regulator. USP20 interacts with and deubiquitinates ERK3 both in vitro and in intact cells. The overexpression of USP20 results in the stabilization and accumulation of the ERK3 protein, whereas USP20 depletion reduces the levels of ERK3. We found that the expression levels of ERK3 correlate with those of USP20 in various cellular contexts. Importantly, we show that USP20 regulates actin cytoskeleton organization and cell migration in a manner dependent on ERK3 expression. Our results identify USP20 as a bona fide regulator of ERK3 stability and physiological functions.