Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity.
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 bothin vitroand 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.
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.|Program of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada.
Simon
S
Mathien
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
Paul
P
Déléris
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
Mathilde
M
Soulez
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
Laure
L
Voisin
Institute of Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada sylvain.meloche@umontreal.ca.|Program of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada.|Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada.
Sylvain
S
Meloche
D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
D034741:RNA, Small Interfering; C459591:USP20 protein, human; D025801:Ubiquitin; D048053:Mitogen-Activated Protein Kinase 6; D000072017:Deubiquitinating Enzymes; D043222:Ubiquitin Thiolesterase
ERK3; MAPKs; deubiquitinating enzymes