This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marchetti, S.
Right arrow Articles by Pagès, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchetti, S.
Right arrow Articles by Pagès, G.

 Previous Article

Molecular and Cellular Biology, January 2005, p. 854-864, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.854-864.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinases Phosphorylate Mitogen-Activated Protein Kinase Phosphatase 3/DUSP6 at Serines 159 and 197, Two Sites Critical for Its Proteasomal Degradation

Sandrine Marchetti ,{dagger},{ddagger} Clotilde Gimond,{dagger}* Jean-Claude Chambard, Thomas Touboul, Danièle Roux, Jacques Pouysségur, and Gilles Pagès

Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, Nice, France

Received 30 April 2004/ Returned for modification 3 June 2004/ Accepted 28 October 2004

Mitogen-activated protein (MAP) kinase phosphatases (MKPs) are dual-specificity phosphatases that dephosphorylate phosphothreonine and phosphotyrosine residues within MAP kinases. Here, we describe a novel posttranslational mechanism for regulating MKP-3/Pyst1/DUSP6, a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation. Using a fibroblast model in which the expression of either MKP-3 or a more stable MKP-3-green fluorescent protein (GFP) chimera was induced by tetracycline, we found that serum induces the phosphorylation of MKP-3 and its subsequent degradation by the proteasome in a MEK1 and MEK2 (MEK1/2)-ERK1/2-dependent manner. In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197. Tetracycline-inducible cell clones expressing either single or double serine mutants of MKP-3 or MKP-3-GFP confirmed that these two sites are targeted by the MEK1/2-ERK1/2 module in vivo. Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. Hence, double mutation caused a threefold increase in the half-life of MKP-3. Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity. Thus, ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol, a situation opposite to that described for the nuclear phosphatase MKP-1.

* Corresponding author. Mailing address: Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, 33 Ave. de Valombrose, 06189 Nice, France. Phone: (33) 492 03 12 31. Fax: (33) 492 03 12 35. E-mail: gimond{at}unice.fr.

{dagger} S.M. and C.G. contributed equally to this work.

{ddagger} Present address: INSERM U526, Physiopathologie de la Survie et de la Mort Cellulaires et Infections Virales, 06107 Nice, France.

Molecular and Cellular Biology, January 2005, p. 854-864, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.854-864.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lonne, G. K., Masoumi, K. C., Lennartsson, J., Larsson, C. (2009). Protein Kinase C{delta} Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway. J. Biol. Chem. 284: 33456-33465 [Abstract] [Full Text]  
  • Nagelin, M. H., Srinivasan, S., Nadler, J. L., Hedrick, C. C. (2009). Murine 12/15-Lipoxygenase Regulates ATP-binding Cassette Transporter G1 Protein Degradation through p38- and JNK2-dependent Pathways. J. Biol. Chem. 284: 31303-31314 [Abstract] [Full Text]  
  • Okudela, K., Yazawa, T., Woo, T., Sakaeda, M., Ishii, J., Mitsui, H., Shimoyamada, H., Sato, H., Tajiri, M., Ogawa, N., Masuda, M., Takahashi, T., Sugimura, H., Kitamura, H. (2009). Down-Regulation of DUSP6 Expression in Lung Cancer: Its Mechanism and Potential Role in Carcinogenesis. Am. J. Pathol. 175: 867-881 [Abstract] [Full Text]  
  • Jurek, A., Amagasaki, K., Gembarska, A., Heldin, C.-H., Lennartsson, J. (2009). Negative and Positive Regulation of MAPK Phosphatase 3 Controls Platelet-derived Growth Factor-induced Erk Activation. J. Biol. Chem. 284: 4626-4634 [Abstract] [Full Text]  
  • Sen, A., Lv, L., Bello, N., Ireland, J. J., Smith, G. W. (2008). Cocaine- and Amphetamine-Regulated Transcript Accelerates Termination of Follicle-Stimulating Hormone-Induced Extracellularly Regulated Kinase 1/2 and Akt Activation by Regulating the Expression and Degradation of Specific Mitogen-Activated Protein Kinase Phosphatases in Bovine Granulosa Cells. Mol. Endocrinol. 22: 2655-2676 [Abstract] [Full Text]  
  • Boutros, T., Chevet, E., Metrakos, P. (2008). Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer. Pharmacol. Rev. 60: 261-310 [Abstract] [Full Text]  
  • Chan, D. W., Liu, V. W.S., Tsao, G. S.W., Yao, K.-M., Furukawa, T., Chan, K. K.L., Ngan, H. Y.S. (2008). Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis 29: 1742-1750 [Abstract] [Full Text]  
  • Morrison, D. J., Kim, M. K.H., Berkofsky-Fessler, W., Licht, J. D. (2008). WT1 Induction of Mitogen-Activated Protein Kinase Phosphatase 3 Represents a Novel Mechanism of Growth Suppression. Mol Cancer Res 6: 1225-1231 [Abstract] [Full Text]  
  • Mortensen, O. V., Larsen, M. B., Prasad, B. M., Amara, S. G. (2008). Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking. Mol. Biol. Cell 19: 2818-2829 [Abstract] [Full Text]  
  • Vogt, A., McDonald, P. R., Tamewitz, A., Sikorski, R. P., Wipf, P., Skoko, J. J. III, Lazo, J. S. (2008). A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Molecular Cancer Therapeutics 7: 330-340 [Abstract] [Full Text]  
  • Oppenheimer, O., Cheung, N.-K., Gerald, W. L. (2007). The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Molecular Cancer Therapeutics 6: 1300-1309 [Abstract] [Full Text]  
  • Wattenberg, E. V. (2007). Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis. Am. J. Physiol. Cell Physiol. 292: C24-C32 [Abstract] [Full Text]  
  • Zhou, B., Zhang, J., Liu, S., Reddy, S., Wang, F., Zhang, Z.-Y. (2006). Mapping ERK2-MKP3 Binding Interfaces by Hydrogen/Deuterium Exchange Mass Spectrometry. J. Biol. Chem. 281: 38834-38844 [Abstract] [Full Text]  
  • Choi, B.-H., Hur, E.-M., Lee, J.-H., Jun, D.-J., Kim, K.-T. (2006). Protein kinase C{delta}-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. J. Cell Sci. 119: 1329-1340 [Abstract] [Full Text]  
  • Ouyang, B., Knauf, J. A., Smith, E. P., Zhang, L., Ramsey, T., Yusuff, N., Batt, D., Fagin, J. A. (2006). Inhibitors of Raf Kinase Activity Block Growth of Thyroid Cancer Cells with RET/PTC or BRAF Mutations In vitro and In vivo.. Clin. Cancer Res. 12: 1785-1793 [Abstract] [Full Text]  
  • Katou, S., Karita, E., Yamakawa, H., Seo, S., Mitsuhara, I., Kuchitsu, K., Ohashi, Y. (2005). Catalytic Activation of the Plant MAPK Phosphatase NtMKP1 by Its Physiological Substrate Salicylic Acid-induced Protein Kinase but Not by Calmodulins. J. Biol. Chem. 280: 39569-39581 [Abstract] [Full Text]  
  • Tarrega, C., Rios, P., Cejudo-Marin, R., Blanco-Aparicio, C., van den Berk, L., Schepens, J., Hendriks, W., Tabernero, L., Pulido, R. (2005). ERK2 Shows a Restrictive and Locally Selective Mechanism of Recognition by Its Tyrosine Phosphatase Inactivators Not Shared by Its Activator MEK1. J. Biol. Chem. 280: 37885-37894 [Abstract] [Full Text]  
  • Nyunoya, T., Monick, M. M., Powers, L. S., Yarovinsky, T. O., Hunninghake, G. W. (2005). Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation. J. Biol. Chem. 280: 26295-26302 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»