A Mek1-Mek2 Heterodimer Determines the Strength and Duration of the Erk Signal

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2009 Feb 17

PMID 19219045

Citations 80

Authors

Federica Catalanotti

Gloria Reyes

Veronika Jesenberger

Gergana Galabova-Kovacs

Ricardo De Matos Simoes

Oliviero Carugo

Manuela Baccarini

Affiliations

Soon will be listed here.

Abstract

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.

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References

Hayashi S, Lewis P, Pevny L, McMahon A . Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev. 2003; 119 Suppl 1:S97-S101. DOI: 10.1016/s0925-4773(03)00099-6. View

Belanger L, Roy S, Tremblay M, Brott B, Steff A, Mourad W . Mek2 is dispensable for mouse growth and development. Mol Cell Biol. 2003; 23(14):4778-87. PMC: 162209. DOI: 10.1128/MCB.23.14.4778-4787.2003. View

Armant D . Blastocysts don't go it alone. Extrinsic signals fine-tune the intrinsic developmental program of trophoblast cells. Dev Biol. 2005; 280(2):260-80. PMC: 2715296. DOI: 10.1016/j.ydbio.2005.02.009. View

Davies H, Bignell G, Cox C, Stephens P, Edkins S, Clegg S . Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-54. DOI: 10.1038/nature00766. View

Scholl F, Dumesic P, Barragan D, Harada K, Bissonauth V, Charron J . Mek1/2 MAPK kinases are essential for Mammalian development, homeostasis, and Raf-induced hyperplasia. Dev Cell. 2007; 12(4):615-29. DOI: 10.1016/j.devcel.2007.03.009. View

Weber C, Slupsky J, Kalmes H, Rapp U . Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 2001; 61(9):3595-8. View

Pike A, Rellos P, Niesen F, Turnbull A, Oliver A, Parker S . Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites. EMBO J. 2008; 27(4):704-14. PMC: 2239268. DOI: 10.1038/emboj.2008.8. View

Rossomando A, Dent P, Sturgill T, Marshak D . Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation. Mol Cell Biol. 1994; 14(3):1594-602. PMC: 358518. DOI: 10.1128/mcb.14.3.1594-1602.1994. View

Bissonauth V, Roy S, Gravel M, Guillemette S, Charron J . Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Development. 2006; 133(17):3429-40. DOI: 10.1242/dev.02526. View

10.

Slack-Davis J, Eblen S, Zecevic M, Boerner S, Tarcsafalvi A, Diaz H . PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol. 2003; 162(2):281-91. PMC: 2172784. DOI: 10.1083/jcb.200212141. View

11.

Brummer T, Naegele H, Reth M, Misawa Y . Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf. Oncogene. 2003; 22(55):8823-34. DOI: 10.1038/sj.onc.1207185. View

12.

Brunet A, Pages G, Pouyssegur J . Growth factor-stimulated MAP kinase induces rapid retrophosphorylation and inhibition of MAP kinase kinase (MEK1). FEBS Lett. 1994; 346(2-3):299-303. DOI: 10.1016/0014-5793(94)00475-7. View

13.

Santos S, Verveer P, Bastiaens P . Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol. 2007; 9(3):324-30. DOI: 10.1038/ncb1543. View

14.

Ohren J, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P . Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004; 11(12):1192-7. DOI: 10.1038/nsmb859. View

15.

Fukuda M, Gotoh I, Adachi M, Gotoh Y, Nishida E . A novel regulatory mechanism in the mitogen-activated protein (MAP) kinase cascade. Role of nuclear export signal of MAP kinase kinase. J Biol Chem. 1998; 272(51):32642-8. DOI: 10.1074/jbc.272.51.32642. View

16.

Schaeffer H, Catling A, Eblen S, Collier L, Krauss A, Weber M . MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science. 1998; 281(5383):1668-71. DOI: 10.1126/science.281.5383.1668. View

17.

Katoh K, Misawa K, Kuma K, Miyata T . MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 2002; 30(14):3059-66. PMC: 135756. DOI: 10.1093/nar/gkf436. View

18.

Xu B, Wilsbacher J, Collisson T, Cobb M . The N-terminal ERK-binding site of MEK1 is required for efficient feedback phosphorylation by ERK2 in vitro and ERK activation in vivo. J Biol Chem. 1999; 274(48):34029-35. DOI: 10.1074/jbc.274.48.34029. View

19.

Giroux S, Tremblay M, Bernard D, Aubry S, Larouche L, Rousseau S . Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol. 1999; 9(7):369-72. DOI: 10.1016/s0960-9822(99)80164-x. View

20.

Harding A, Hancock J . Ras nanoclusters: combining digital and analog signaling. Cell Cycle. 2008; 7(2):127-34. PMC: 2782570. DOI: 10.4161/cc.7.2.5237. View