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© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
Specificity Determinants in MAPK Signaling to Transcription Factors* §¶,§ **, and
From the 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.
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: a.d.sharrocks@man.ac.uk.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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