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Mol. Cell. Biol. 23 (13): 4542-4558

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Rapid Turnover of Extracellular Signal-Regulated Kinase 3 by the Ubiquitin-Proteasome Pathway Defines a Novel Paradigm of Mitogen-Activated Protein Kinase Regulation during Cellular Differentiation

Philippe Coulombe,1,2 Geneviève Rodier,1 Stéphane Pelletier,1,3 Johanne Pellerin,1 and Sylvain Meloche1,2,3*

Institut de Recherches Cliniques de Montréal,1 Departments of Molecular Biology,2 Pharmacology, Université de Montréal, Montreal, Quebec H2W 1R7, Canada3

Received for publication 23 September 2002. Revision received 6 November 2002. Accepted for publication 31 March 2003.

Abstract: Mitogen-activated protein (MAP) kinases are stable enzymes that are mainly regulated by phosphorylation and subcellular targeting. Here we report that extracellular signal-regulated kinase 3 (ERK3), unlike other MAP kinases, is an unstable protein that is constitutively degraded in proliferating cells with a half-life of 30 min. The proteolysis of ERK3 is executed by the proteasome and requires ubiquitination of the protein. Contrary to other protein kinases, the catalytic activity of ERK3 is not responsible for its short half-life. Instead, analysis of ERK1/ERK3 chimeras revealed the presence of two destabilization regions (NDR1 and -2) in the N-terminal lobe of the ERK3 kinase domain that are both necessary and sufficient to target ERK3 and heterologous proteins for proteasomal degradation. To assess the physiological relevance of the rapid turnover of ERK3, we monitored the expression of the kinase in different cellular models of differentiation. We observed that ERK3 markedly accumulates during differentiation of PC12 and C2C12 cells into the neuronal and muscle lineage, respectively. The accumulation of ERK3 during myogenic differentiation is associated with the time-dependent stabilization of the protein. Terminal skeletal muscle differentiation is accompanied by cell cycle withdrawal. Interestingly, we found that expression of stabilized forms of ERK3 causes G1 arrest in NIH 3T3 cells. We propose that ERK3 biological activity is regulated by its cellular abundance through the control of protein stability.

* Corresponding author. Mailing address: Institut de Recherches Cliniques de Montréal, 110 Pine Ave., West, Montreal, Quebec H2W 1R7, Canada. Phone: (514) 987-5783. Fax: (514) 987-5536. E-mail: melochs{at}ircm.qc.ca.

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