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Originally published In Press as doi:10.1074/jbc.M010271200 on December 28, 2000

J. Biol. Chem., Vol. 276, Issue 13, 10374-10386, March 30, 2001
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A Conserved Docking Site in MEKs Mediates High-affinity Binding to MAP Kinases and Cooperates with a Scaffold Protein to Enhance Signal Transmission*

A. Jane BardwellDagger , Laura J. FlatauerDagger , Karen MatsukumaDagger , Jeremy Thorner§, and Lee BardwellDagger

From the Dagger  Department of Developmental and Cell Biology, University of California, Irvine, California 92697 and the § Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Berkeley, California 94720-3202

The recognition of mitogen-activated protein kinases (MAPKs) by their upstream activators, MAPK/ERK kinases (MEKs), is crucial for the effective and accurate transmission of many signals. We demonstrated previously that the yeast MAPKs Kss1 and Fus3 bind with high affinity to the N terminus of the MEK Ste7, and proposed that a conserved motif in Ste7, the MAPK-docking site, mediates this interaction. Here we show that the corresponding sequences in human MEK1 and MEK2 are necessary and sufficient for the direct binding of the MAPKs ERK1 and ERK2. Mutations in MEK1, MEK2, or Ste7 that altered conserved residues in the docking site diminished binding of the cognate MAPKs. Furthermore, short peptides corresponding to the docking sites in these MEKs inhibited MEK1-mediated phosphorylation of ERK2 in vitro. In yeast cells, docking-defective alleles of Ste7 were modestly compromised in their ability to transmit the mating pheromone signal. This deficiency was dramatically enhanced when the ability of the Ste5 scaffold protein to associate with components of the MAPK cascade was also compromised. Thus, both the MEK-MAPK docking interaction and binding to the Ste5 scaffold make mutually reinforcing contributions to the efficiency of signaling by this MAPK cascade in vivo.

* This work was supported by a Special Fellow Award from the Leukemia and Lymphoma Society (to L. B.) (work done at Berkeley), National Institutes of Health Research Grant GM21841 (to J. T.), resources provided by the Berkeley Campus Cancer Research Laboratory; and a Burroughs Wellcome Foundation New Investigator Award, Beckman Foundation Young Investigator Award, by seed money provided by Grant IRG 98-279 from the American Cancer Society, and National Institutes of Health Research Grant GM60366 (all to L. B.) (work done at Irvine).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.

To whom correspondence should be addressed: Dept. of Developmental and Cell Biology, 5207 Biological Sciences II, University of California, Irvine, CA 92697-2300. Tel.: 949-824-6902; Fax: 949-824-4709; E-mail: bardwell@uci.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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