Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ubiquitination and the Ubiquitin - Proteasome System in the Pathogenesis and Treatment of Squamous Head and Neck Carcinoma.
I. A. VOUTSADAKIS (2013)
Anticancer Res 33, 3527-3541
   Abstract »    Full Text »    PDF »
Robustness and Compensation of Information Transmission of Signaling Pathways.
S. Uda, T. H. Saito, T. Kudo, T. Kokaji, T. Tsuchiya, H. Kubota, Y. Komori, Y.-i. Ozaki, and S. Kuroda (2013)
Science 341, 558-561
   Abstract »    Full Text »    PDF »
Identification and Proteomic Analysis of Distinct UBE3A/E6AP Protein Complexes.
G. Martinez-Noel, J. T. Galligan, M. E. Sowa, V. Arndt, T. M. Overton, J. W. Harper, and P. M. Howley (2012)
Mol. Cell. Biol. 32, 3095-3106
   Abstract »    Full Text »    PDF »
Iron Regulatory Protein 2 Turnover through a Nonproteasomal Pathway.
A. H. K. Chang, J. Jeong, and R. L. Levine (2011)
J. Biol. Chem. 286, 23698-23707
   Abstract »    Full Text »    PDF »
Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases.
M. Cargnello and P. P. Roux (2011)
Microbiol. Mol. Biol. Rev. 75, 50-83
   Abstract »    Full Text »    PDF »
Activation Loop Phosphorylation of ERK3/ERK4 by Group I p21-activated Kinases (PAKs) Defines a Novel PAK-ERK3/4-MAPK-activated Protein Kinase 5 Signaling Pathway.
P. Deleris, M. Trost, I. Topisirovic, P.-L. Tanguay, K. L. B. Borden, P. Thibault, and S. Meloche (2011)
J. Biol. Chem. 286, 6470-6478
   Abstract »    Full Text »    PDF »
Targeted Inactivation of Mapk4 in Mice Reveals Specific Nonredundant Functions of Erk3/Erk4 Subfamily Mitogen-Activated Protein Kinases.
J. Rousseau, S. Klinger, A. Rachalski, B. Turgeon, P. Deleris, E. Vigneault, J.-F. Poirier-Heon, M. A. Davoli, N. Mechawar, S. El Mestikawy, et al. (2010)
Mol. Cell. Biol. 30, 5752-5763
   Abstract »    Full Text »    PDF »
Uncoupling of Expression of an Intronic MicroRNA and Its Myosin Host Gene by Exon Skipping.
M. L. Bell, M. Buvoli, and L. A. Leinwand (2010)
Mol. Cell. Biol. 30, 1937-1945
   Abstract »    Full Text »    PDF »
Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality.
S. Klinger, B. Turgeon, K. Levesque, G. A. Wood, K. M. Aagaard-Tillery, and S. Meloche (2009)
PNAS 106, 16710-16715
   Abstract »    Full Text »    PDF »
Docking of PRAK/MK5 to the Atypical MAPKs ERK3 and ERK4 Defines a Novel MAPK Interaction Motif.
E. Aberg, K. M. Torgersen, B. Johansen, S. M. Keyse, M. Perander, and O.-M. Seternes (2009)
J. Biol. Chem. 284, 19392-19401
   Abstract »    Full Text »    PDF »
Participation of the Human Sperm Proteasome in the Capacitation Process and Its Regulation by Protein Kinase A and Tyrosine Kinase.
M. Kong, E. S. Diaz, and P. Morales (2009)
Biol Reprod 80, 1026-1035
   Abstract »    Full Text »    PDF »
Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination: Insights From Model Organisms.
Y. Wang and H. G. Dohlman (2006)
Circ. Res. 99, 1305-1314
   Abstract »    Full Text »    PDF »
Regulation of MAPK-activated Protein Kinase 5 Activity and Subcellular Localization by the Atypical MAPK ERK4/MAPK4.
E. Aberg, M. Perander, B. Johansen, C. Julien, S. Meloche, S. M. Keyse, and O.-M. Seternes (2006)
J. Biol. Chem. 281, 35499-35510
   Abstract »    Full Text »    PDF »
Characterization of the Atypical MAPK ERK4 and Its Activation of the MAPK-activated Protein Kinase MK5.
S. Kant, S. Schumacher, M. K. Singh, A. Kispert, A. Kotlyarov, and M. Gaestel (2006)
J. Biol. Chem. 281, 35511-35519
   Abstract »    Full Text »    PDF »
Involvement of the I{kappa}B Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation.
A. Bibeau-Poirier, S.-P. Gravel, J.-F. Clement, S. Rolland, G. Rodier, P. Coulombe, J. Hiscott, N. Grandvaux, S. Meloche, and M. J. Servant (2006)
J. Immunol. 177, 5059-5067
   Abstract »    Full Text »    PDF »
Ubiquitin-Proteasome-mediated Degradation, Intracellular Localization, and Protein Synthesis of MyoD and Id1 during Muscle Differentiation.
L. Sun, J. S. Trausch-Azar, A. Ciechanover, and A. L. Schwartz (2005)
J. Biol. Chem. 280, 26448-26456
   Abstract »    Full Text »    PDF »
Ubiquitin Chains in the Ladder of MAPK Signaling.
A. Laine and Z. Ronai (2005)
Sci. STKE 2005, re5
   Abstract »    Full Text »    PDF »
The Ubiquitin-Proteasome Pathway is Involved in Rapid Degradation of Phosphoenolpyruvate Carboxylase Kinase for C4 Photosynthesis.
M. Agetsuma, T. Furumoto, S. Yanagisawa, and K. Izui (2005)
Plant Cell Physiol. 46, 389-398
   Abstract »    Full Text »    PDF »
p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2.
G. Rodier, C. Makris, P. Coulombe, A. Scime, K. Nakayama, K. I. Nakayama, and S. Meloche (2005)
J. Cell Biol. 168, 55-66
   Abstract »    Full Text »    PDF »
Scaffolding by ERK3 regulates MK5 in development.
S. Schumacher, K. Laass, S. Kant, Y. Shi, A. Visel, A. D. Gruber, A. Kotlyarov, and M. Gaestel (2004)
EMBO J. 23, 4770-4779
   Abstract »    Full Text »    PDF »
Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway.
O.-M. Seternes, T. Mikalsen, B. Johansen, E. Michaelsen, C. G. Armstrong, N. A. Morrice, B. Turgeon, S. Meloche, U. Moens, and S. M. Keyse (2004)
EMBO J. 23, 4780-4791
   Abstract »    Full Text »    PDF »
Protein Phosphatase 4 Is a Positive Regulator of Hematopoietic Progenitor Kinase 1.
G. Zhou, J. S. Boomer, and T.-H. Tan (2004)
J. Biol. Chem. 279, 49551-49561
   Abstract »    Full Text »    PDF »
N-Terminal Ubiquitination of Extracellular Signal-Regulated Kinase 3 and p21 Directs Their Degradation by the Proteasome.
P. Coulombe, G. Rodier, E. Bonneil, P. Thibault, and S. Meloche (2004)
Mol. Cell. Biol. 24, 6140-6150
   Abstract »    Full Text »    PDF »
ERK7 Expression and Kinase Activity Is Regulated by the Ubiquitin-Proteosome Pathway.
W.-L. Kuo, C. J. Duke, M. K. Abe, E. L. Kaplan, S. Gomes, and M. R. Rosner (2004)
J. Biol. Chem. 279, 23073-23081
   Abstract »    Full Text »    PDF »
Nuclear Export of ERK3 by a CRM1-dependent Mechanism Regulates Its Inhibitory Action on Cell Cycle Progression.
C. Julien, P. Coulombe, and S. Meloche (2003)
J. Biol. Chem. 278, 42615-42624
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882