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J. Biol. Chem., Vol. 280, Issue 27, 25651-25658, July 8, 2005

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Dynamic Interaction between the Dual Specificity Phosphatase MKP7 and the JNK3 Scaffold Protein -Arrestin 2^*

Emma A. Willoughby and Mary K. Collins

From the Division of Infection and Immunity, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, United Kingdom

JNK scaffold proteins bind JNK and upstream kinases to activate subsets of JNK and localize activated JNK to specific subcellular sites. We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1). The G protein-coupled receptor (GPCR) adaptor -arrestin 2 is also a JNK3 scaffold. It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3. Here we report that MKP7 also binds -arrestin 2 via amino acids 394–443 of MKP7, the same region that interacts with JIP-1. This region of MKP7 interacts with -arrestin 2 at a central region near the JNK binding domain. MKP7 dephosphorylates JNK3 bound to -arrestin 2, either following activation by ASK1 overexpression or following AT1aR stimulation. Initial AT1aR stimulation causes a rapid (within 5 min) dissociation of MKP7 from -arrestin 2. MKP7 then reassociates with -arrestin 2 on endocytic vesicles 30–60 min after initial receptor stimulation. This dynamic interaction between phosphatase and scaffold permits signal transduction through a module that binds both positive and negative regulators.

Received for publication, February 22, 2005 , and in revised form, April 13, 2005.

^* This work was supported by the Association for International Cancer Research. 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.

To whom correspondence should be addressed: Div. of Infection and Immunity, Windeyer Bldg., 46 Cleveland St, London W1T 4JF, UK. Tel./Fax: 44-207679-9301; E-mail: mary.collins{at}ucl.ac.uk.

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