p-T,Y MAPKs dimerize

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R-HSA-5674385
Type
Reaction [transition]
Species
Homo sapiens
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Phosphorylated MAPK monomers can dimerize - generally into MAPK1 and MAPK3 homodimers, as the heterodimer is unstable- but the physiological significance of dimerization is unclear (Khokhlatchev et al, 1998; reviewed Rosokoski, 2012b). MAPKs have both cytosolic and nuclear targets and dimerization may be particularly important for MAPK-dependent phosphorylation of cytosolic targets. Phosphorylation of cytosolic MAPK targets appears to happen predominantly in the context of larger scaffolding complexes, and since the scaffolds and cytosolic MAPK substrates contact the same hydrophobic surface of MAPK, dimerization is necessary to allow assembly of a functional complex (Casar et al, 2008; Lidke et al, 2010; reviewed in Casar et al, 2009). Consistent with this, disrupting either MAPK dimerization or the MAPK interaction with the scaffolding protein abrogated proliferation and transformation (Casar et al, 2008). Note that, for simplicity in this diagram, dimerization is shown as happening between free cytosolic monomers of activated MAPK rather than in the context of the scaffolding complex.
Although predominantly cytoplasmic in resting cells, a proportion of activated MAPK translocates to the nucleus upon stimulation where it activates nuclear targets. Despite early studies to the suggesting that dimerization was required for nuclear translocation, a few recent papers have challenged this notion (Lenormand et al, 1993; Chen et al, 1992; Khokhlatchev et al, 1998; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Roskoski, 2012b).

Literature References
PubMed ID Title Journal Year
1545823 Nuclear localization and regulation of erk- and rsk-encoded protein kinases

Chen, RH, Sarnecki, C, Blenis, J

Mol. Cell. Biol. 1992
22569528 ERK1/2 MAP kinases: structure, function, and regulation

Roskoski, R Jr

Pharmacol. Res. 2012
8394845 Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts

Lenormand, P, Sardet, C, Pagès, G, L'Allemain, G, Brunet, A, Pouysségur, J

J. Cell Biol. 1993
18775330 Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes

Casar, B, Pinto, A, Crespo, P

Mol. Cell 2008
15546878 Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK

Burack, WR, Shaw, AS

J. Biol. Chem. 2005
9604935 Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation

Khokhlatchev, AV, Canagarajah, B, Wilsbacher, J, Robinson, M, Atkinson, M, Goldsmith, E, Cobb, MH

Cell 1998
19920141 ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation

Lidke, DS, Huang, F, Post, JN, Rieger, B, Wilsbacher, J, Thomas, JL, Pouysségur, J, Jovin, TM, Lenormand, P

J. Biol. Chem. 2010
19279408 ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task

Casar, B, Pinto, A, Crespo, P

Cell Cycle 2009
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