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J. Biol. Chem., Vol. 278, Issue 10, 8118-8125, March 7, 2003

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Negative Regulation of MAPKK by Phosphorylation of a Conserved Serine Residue Equivalent to Ser²¹² of MEK1^*

Kailesh Gopalbhai, Gregor Jansen^§¶, Geneviève Beauregard, Malcolm Whiteway^§, France Dumas^§, Cunle Wu^§, and Sylvain Meloche^**

From the  Institut de Recherches Cliniques de Montréal and the Department of Pharmacology, Université de Montréal, Montreal, Quebec H2W 1R7, Canada, the ^§ Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada, and the  Biology Department, McGill University, Montreal, Quebec H3A 1B1, Canada

The MAPKKs MEK1 and MEK2 are activated by phosphorylation, but little is known about how these enzymes are inactivated. Here, we show that MEK1 is phosphorylated in vivo at Ser²¹², a residue conserved among all MAPKK family members. Mutation of Ser²¹² to alanine enhanced the basal activity of MEK1, whereas the phosphomimetic aspartate mutation completely suppressed the activation of both wild-type MEK1 and the constitutively activated MEK1(S218D/S222D) mutant. Phosphorylation of Ser²¹² did not interfere with activating phosphorylation of MEK1 at Ser²¹⁸/Ser²²² or with binding to ERK2 substrate. Importantly, mimicking phosphorylation of the equivalent Ser²¹² residue of the yeast MAPKKs Pbs2p and Ste7p similarly abrogated their biological function. Our findings suggest that Ser²¹² phosphorylation represents an evolutionarily conserved mechanism involved in the negative regulation of MAPKKs.

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