A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal.
Mek1 and Mek2 (also known as Map2k1 and Map2k2, respectively) are evolutionarily conserved, dual-specificity kinases that mediate Erk1 and Erk2 activation during adhesion and growth factor signaling. Here we describe a previously uncharacterized, unexpected role of Mek1 in downregulating Mek2-dependent Erk signaling. Mek1 mediates the regulation of Mek2 in the context of a previously undiscovered Mek1-Mek2 complex. The Mek heterodimer is negatively regulated by Erk-mediated phosphorylation of Mek1 on Thr292, a residue missing in Mek2. Disabling this Erk-proximal negative-feedback step stabilizes the phosphorylation of both Mek2 and Erk in cultured cells and in vivo in Mek1 knockout embryos and mice. Thus, in disagreement with the current perception of the pathway, the role of Mek1 and Mek2 in growth factor-induced Erk phosphorylation is not interchangeable. Our data establish Mek1 as the crucial modulator of Mek and Erk signaling and have potential implications for the role of Mek1 and Mek2 in tumorigenesis.
Catalanotti
Federica
F
Max F. Perutz Laboratories, University of Vienna, Doktor-Bohr-Gasse 9, 1030 Vienna, Austria.
Reyes
Gloria
G
Jesenberger
Veronika
V
Galabova-Kovacs
Gergana
G
de Matos Simoes
Ricardo
R
Carugo
Oliviero
O
Baccarini
Manuela
M
D000818:Animals; D019281:Dimerization; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D020836:Protein Structure, Quaternary
D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse