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J. Biol. Chem., Vol. 281, Issue 19, 13169-13179, May 12, 2006

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Interacting JNK-docking Sites in MKK7 Promote Binding and Activation of JNK Mitogen-activated Protein Kinases^*

From the Department of Developmental and Cell Biology, University of California, Irvine, California 92697

D-sites are a class of MAPK-docking sites that have been found in many MAPK regulators and substrates. A single functional, high affinity D-site has been identified near the N terminus of each of the MAPK kinases (MKKs or MEKs) MEK1, MEK2, MKK3, MKK4, and MKK6. Here we demonstrated that MKK7 recognizes its target JNK by a novel mechanism involving a partially cooperative interaction of three low affinity D-sites in the N-terminal domain of MKK7. Mutations of the conserved residues within any one of the three docking sites (D1, D2, and D3) disrupted the ability of the N-terminal domain of MKK7 to bind JNK1 by about 50–70%. Moreover, mutation of any two of the three D-sites reduced binding by about 80–90%, and mutation of all three reduced binding by 95%. Full-length MKK7 containing combined D1/D2 mutations was compromised for binding to JNK1 and exhibited reduced JNK1 kinase activity when compared with wild-type MKK7. Peptide versions of the D-sites from MKK4 or the JIP-1 scaffold protein inhibited MKK7-JNK binding, suggesting that all three JNK regulators bind to the same region of JNK. Moreover, peptide versions of any of the three D-sites of MKK7 inhibited the ability of JNK1 and JNK2 to phosphorylate their transcription factor substrates c-Jun and ATF2, suggesting that D-site-containing substrates also compete with MKK7 for docking to JNK. Finally, MKK7-derived D-site peptides exhibited selective inhibition of JNK1 versus ERK2. We conclude that MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity.

Received for publication, February 2, 2006 , and in revised form, March 9, 2006.

^* This work was supported in part by NIGMS Research Grant GM60366 from the National Institutes of Health. 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 in part by National Library of Medicine Training Grant LM07443.

² Supported in part by a postdoctoral fellowship from the Philip Morris External Research Program and a grant from the Milheim Foundation.

³ To whom correspondence should be addressed: Dept. of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300. Tel.: 949-824-6902; Fax: 949-824-4709; E-mail: bardwell{at}uci.edu.

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