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J. Biol. Chem. 277 (12): 9896-9903

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Specificity Determinants in MAPK Signaling to Transcription Factors*

Dalia Barsyte-LovejoyDagger §, Alex GalanisDagger §||**, and Andrew D. SharrocksDagger Dagger Dagger

From the Dagger  School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom and the || School of Biochemistry and Genetics, Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE2 4HH, United Kingdom

One critical component in determining the specificity, fidelity, and efficiency of MAPK substrate phosphorylation is the presence of distinct docking domains in the substrate proteins. These docking domains are found in a range of substrates, including the transcription factors myocyte enhancer factor-2A and SAP-1. However, the sequences of these motifs differ, as does their targeting preferences by MAPKs, with SAP-1 being targeted by both the ERK and p38 isoforms, whereas myocyte enhancer factor-2A is targeted only by certain members of the p38 subfamily. Here, we have investigated the specificity determinants within these motifs and generated a model for how specificity is generated. We demonstrate that residues throughout the docking domains play important roles in the recognition process. However, residues located at different positions are important for discriminating between ERK and p38 MAPKs. Furthermore, the docking domains can be further subdivided into submotifs, which are differentially required for phosphorylation by ERK or p38 MAPKs. We have used loss- and gain-of-function mutagenesis to identify residues that discriminate between ERK and p38 MAPKs, residues that act to promote suboptimal interactions, and regions that are differentially required depending on the kinase involved. A model is proposed to explain how specificity is generated within these short docking domains.

* This work was supported by grants from the Cancer Research Campaign and the Wellcome Trust and by a Lister Institute of Preventative Medicine research fellowship (to A. D. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Present address: Ontario Cancer Inst., University of Toronto, 610 University Ave., Toronto, Ontario M5G 2M9, Canada.

** Supported by a Jeffcock Ph.D. studentship from the University of Newcastle Upon Tyne.

Dagger Dagger To whom correspondence should be addressed: School of Biological Sciences, University of Manchester, 2.205 Stopford Bldg., Oxford Rd., Manchester M13 9PT, UK. Tel.: 44-161-275-5979; Fax: 44-161-275-5082; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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