Reactome | p-T,Y MAPKs dimerize

p-T,Y MAPKs dimerize

Stable Identifier

R-HSA-5674385

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Signal Transduction (Homo sapiens)

- MAPK family signaling cascades (Homo sapiens)
  - MAPK1/MAPK3 signaling (Homo sapiens)
    - RAF-independent MAPK1/3 activation (Homo sapiens)
      - p-T,Y MAPKs dimerize (Homo sapiens)
    - RAF/MAP kinase cascade (Homo sapiens)
      - p-T,Y MAPKs dimerize (Homo sapiens)
- Signaling by Receptor Tyrosine Kinases (Homo sapiens)
  - Signaling by NTRKs (Homo sapiens)
    - Signaling by NTRK1 (TRKA) (Homo sapiens)
      - Signalling to ERKs (Homo sapiens)
        
        Prolonged ERK activation events (Homo sapiens)
        
        Frs2-mediated activation (Homo sapiens)
        
        p-T,Y MAPKs dimerize (Homo sapiens)

General

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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
22569528	ERK1/2 MAP kinases: structure, function, and regulation Roskoski, R Jr	Pharmacol. Res.	2012
1545823	Nuclear localization and regulation of erk- and rsk-encoded protein kinases Chen, RH, Sarnecki, C, Blenis, J	Mol. Cell. Biol.	1992
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