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J. Biol. Chem., Vol. 280, Issue 45, 37885-37894, November 11, 2005

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ERK2 Shows a Restrictive and Locally Selective Mechanism of Recognition by Its Tyrosine Phosphatase Inactivators Not Shared by Its Activator MEK1^*

Céline Tárrega1, Pablo Ríos2, Rocío Cejudo-Marín3, Carmen Blanco-Aparicio4, Lieke van den Berk, Jan Schepens, Wiljan Hendriks, Lydia Tabernero¶, and Rafael Pulido5

From the Centro de Investigación Príncipe Felipe, Valencia 46013, Spain, the Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Geert Grooteplein 28, Nijmegen 6525 GA, The Netherlands, and ^¶Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

The two regulatory residues that control the enzymatic activity of the mitogen-activated protein (MAP) kinase ERK2 are phosphorylated by the unique MAP kinase kinases MEK1/2 and dephosphorylated by several tyrosine-specific and dual specificity protein phosphatases. Selective docking interactions facilitate these phosphorylation and dephosphorylation events, controlling the specificity and duration of the MAP kinase activation-inactivation cycles. We have analyzed the contribution of specific residues of ERK2 in the physical and functional interaction with the ERK2 phosphatase inactivators PTP-SL and MKP-3 and with its activator MEK1. Single mutations in ERK2 that abrogated the dephosphorylation by endogenous tyrosine phosphatases from HEK293 cells still allowed efficient phosphorylation by endogenous MEK1/2. Discrete ERK2 mutations at the ERK2 docking groove differentially affected binding and inactivation by PTP-SL and MKP-3. Remarkably, the cytosolic retention of ERK2 by its activator MEK1 was not affected by any of the analyzed ERK2 single amino acid substitutions. A chimeric MEK1 protein, containing the kinase interaction motif of PTP-SL, bound tightly to ERK2 through its docking groove and behaved as a gain-of-function MAP kinase kinase that hyperactivated ERK2. Our results provide evidence that the ERK2 docking groove is more restrictive and selective for its tyrosine phosphatase inactivators than for MEK1/2 and indicate that distinct ERK2 residues modulate the docking interactions with activating and inactivating effectors.

Received for publication, April 21, 2005 , and in revised form, July 29, 2005.

^* This work was supported in part by Ministerio de Ciencia y Tecnología (Spain and European Union) Grant BMC2003-02696 (to R. P.), by European Union Human Potential Program Research Training Network Grant HPRN-CT-2000-00085 (to R. P. and W. H.), and by Biomedical Research Collaboration Grant 069899 from the Wellcome Trust (United Kingdom) (to L. T. and R. P.). 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 Supported by the European Union Human Potential Program.

² Recipient of a predoctoral fellowship from Generalitat Valenciana (Spain).

³ Recipient of a postdoctoral fellowship from Bancaja (Spain).

⁴ Present address: Grupo de Desarrollo de Ensayos, Departamento de Terapias Experimentales, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.

⁵ To whom correspondence should be addressed: Centro de Investigación Príncipe Felipe, Avda. Autopista del Saler 16-3, Valencia 46013, Spain. Tel.: 34-96-3289680; Fax: 34-96-3289701; E-mail: rpulido{at}cipf.es.

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