TY  - JOUR
A1  - Catalanotti, Federica
A1  - Reyes, Gloria Ximena
A1  - Jesenberger, Veronika
A1  - Galabova-Kovacs, Gergana
A1  - de Matos Simoes, Ricardo
A1  - Carugo, Oliviero
A1  - Baccarini, Manuela
T1  - A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal
JF  - Nat Struct Mol Biol.
N2  - 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.
KW  - Mek1-Mek2 pathway
KW  - tumorigenesis
KW  - ERK activation
KW  - cancer biology
Y1  - 2020
VL  - 2009
IS  - 16(3)
SP  - 294
EP  - 303
ER  -