title: Negative regulation of MAPKK by phosphorylation of a conserved serine residue equivalent to Ser212 of MEK1.
abstract: 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 Ser(212), a residue conserved among all MAPKK family members. Mutation of Ser(212) 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 Ser(212) did not interfere with activating phosphorylation of MEK1 at Ser(218)/Ser(222) or with binding to ERK2 substrate. Importantly, mimicking phosphorylation of the equivalent Ser(212) residue of the yeast MAPKKs Pbs2p and Ste7p similarly abrogated their biological function. Our findings suggest that Ser(212) phosphorylation represents an evolutionarily conserved mechanism involved in the negative regulation of MAPKKs.
authors.affiliation: Institut de Recherches Cliniques de Montréal and the Department of Pharmacology, Université de Montréal, Quebec H2W 1R7, Canada.
authors.forename: Kailesh
authors.initials: K
authors.lastname: Gopalbhai
authors.forename: Gregor
authors.initials: G
authors.lastname: Jansen
authors.forename: Geneviève
authors.initials: G
authors.lastname: Beauregard
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whiteway
authors.forename: France
authors.initials: F
authors.lastname: Dumas
authors.forename: Cunle
authors.initials: C
authors.lastname: Wu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism*
chemical_list: D012694:Serine; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases