HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 2, 915-926, January 13, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/2/915    most recent M508720200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, Y.-W. Articles by Yang, J.-L. Search for Related Content PubMed PubMed Citation Articles by Lin, Y.-W. Articles by Yang, J.-L. Social Bookmarking                      What's this?

Cooperation of ERK and SCF^Skp2 for MKP-1 Destruction Provides a Positive Feedback Regulation of Proliferating Signaling^*

From the Molecular Carcinogenesis Laboratory, Institute of Biotechnology, and the Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan

The dual-specificity MAPK phosphatase MKP-1/CL100/DUSP1 is an inducible nuclear protein controlled by p44/42 MAPK (ERK1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain ERK activation by triggering MKP-1 proteolysis. Active ERK2 docking to the DEF motif (FXFP, residues 339–342) of N-terminally truncated MKP-1 in vitro initiated phosphorylation at the Ser²⁹⁶/Ser³²³ domain, which was not affected by substituting Ala for Ser at Ser³⁵⁹/Ser³⁶⁴. The DEF and Ser²⁹⁶/Ser³²³ sites were essential for ubiquitin-mediated MKP-1 proteolysis stimulated by MKK1-ERK signaling in H293 cells, whereas the N-terminal domain and Ser³⁵⁹/Ser³⁶⁴ sites were dispensable. ERK activation by serum increased the endogenous level of ubiquitinated phospho-Ser²⁹⁶ MKP-1 and the degradation of MKP-1. Intriguingly, active ERK-promoted phospho-Ser²⁹⁶ MKP-1 bound to SCF^Skp2 ubiquitin ligase in vivo and in vitro. Forced expression of Skp2 enhanced MKP-1 polyubiquitination and proteolysis upon ERK activation, whereas depletion of endogenous Skp2 suppressed such events. The kinetics of ERK signaling stimulated by serum correlated with the endogenous MKP-1 degradation rate in a Skp2-dependent manner. Thus, MKP-1 proteolysis can be achieved via ERK and SCF^Skp2 cooperation, thereby sustaining ERK activation.

Received for publication, August 8, 2005 , and in revised form, November 10, 2005.

^* This work was supported by National Science Council of Taiwan Grant NSC93-2320-B-007-002. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 886-3-571-5934; Fax: 886-3-571-5934; E-mail: jlyang{at}life.nthu.edu.tw.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. Wang, N. Cao, D. Nantajit, M. Fan, Y. Liu, and J. J. Li Mitogen-activated Protein Kinase Phosphatase-1 Represses c-Jun NH2-terminal Kinase-mediated Apoptosis via NF-{kappa}B Regulation J. Biol. Chem., July 25, 2008; 283(30): 21011 - 21023. [Abstract] [Full Text] [PDF]

				D. L. Sheridan, Y. Kong, S. A. Parker, K. N. Dalby, and B. E. Turk Substrate Discrimination among Mitogen-activated Protein Kinases through Distinct Docking Sequence Motifs J. Biol. Chem., July 11, 2008; 283(28): 19511 - 19520. [Abstract] [Full Text] [PDF]

				D. F. Calvisi, F. Pinna, F. Meloni, S. Ladu, R. Pellegrino, M. Sini, L. Daino, M. M. Simile, M. R. De Miglio, P. Virdis, et al. Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase-Mediated Control of Growth in Human Hepatocellular Carcinoma Cancer Res., June 1, 2008; 68(11): 4192 - 4200. [Abstract] [Full Text] [PDF]

				A. Ito, T. Suganami, Y. Miyamoto, Y. Yoshimasa, M. Takeya, Y. Kamei, and Y. Ogawa Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy J. Biol. Chem., August 31, 2007; 282(35): 25445 - 25452. [Abstract] [Full Text] [PDF]

				E. Sanchez-Tillo, M. Comalada, J. Xaus, C. Farrera, A. F. Valledor, C. Caelles, J. Lloberas, and A. Celada JNK1 Is Required for the Induction of Mkp1 Expression in Macrophages during Proliferation and Lipopolysaccharide-dependent Activation J. Biol. Chem., April 27, 2007; 282(17): 12566 - 12573. [Abstract] [Full Text] [PDF]

				Y. Kim and E. T. Kipreos The Caenorhabditis elegans Replication Licensing Factor CDT-1 Is Targeted for Degradation by the CUL-4/DDB-1 Complex Mol. Cell. Biol., February 15, 2007; 27(4): 1394 - 1406. [Abstract] [Full Text] [PDF]