Depending upon the stimulus and cell type mitogen-activated protein kinases (MAPK) signaling pathway can transmit signals to regulate many different biological processes by virtue of their ability to target multiple effector proteins (Kyriakis JM & Avruch J 2012; Yoon and Seger 2006; Shaul YD & Seger R 2007; Arthur JS & Ley SC 2013). In particular, the extracellular signal-regulated kinases MAPK3(ERK1) and MAPK1 (ERK2) are involved in diverse cellular processes such as proliferation, differentiation, regulation of inflammatory responses, cytoskeletal remodeling, cell motility and invasion through the increase of matrix metalloproteinase production (Viala E & Pouyssegur J 2004; Hsu MC et al. 2006; Dawson CW et al.2008; Kuriakose T et al. 2014).The canonical RAF:MAP2K:MAPK1/3 cascade is stimulated by various extracellular stimuli including hormones, cytokines, growth factors, heat shock and UV irradiation triggering the GEF-mediated activation of RAS at the plasma membrane and leading to the activation of the RAF MAP3 kinases. However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS (Dawson CW et al. 2008; Wang J et al. 2009; Kuriakose T et al. 2014). For example, AMP-activated protein kinase (AMPK), but not RAF1, was reported to regulate MAP2K1/2 and MAPK1/3 (MEK and ERK) activation in rat hepatoma H4IIE and human erythroleukemia K562 cells in response to autophagy stimuli (Wang J et al. 2009). Tumor progression locus 2 (TPL2, also known as MAP3K8 and COT) is another MAP3 kinase which promotes MAPK1/3 (ERK)-regulated immune responses downstream of toll-like receptors (TLR), TNF receptor and IL1beta signaling pathways (Gantke T et al. 2011).
In response to stimuli the cell surface receptors transmit signals inducing MAP3 kinases, e.g., TPL2, MEKK1, which in turn phosphorylate MAP2Ks (MEK1/2). MAP2K then phosphorylate and activate the MAPK1/3 (ERK1 and ERK2 MAPKs). Activated MAPK1/3 phosphorylate and regulate the activities of an ever growing pool of substrates that are estimated to comprise over 160 proteins (Yoon and Seger 2006). The majority of ERK substrates are nuclear proteins, but others are found in the cytoplasm and other organelles. Activated MAPK1/3 can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, such as Ets family transcription factors (e.g., ELK1), ultimately leading to changes in gene expression (Zuber J et al. 2000).
View original pathway at Reactome.</div>
Gantke T, Sriskantharajah S, Ley SC.; ''Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase.''; PubMedEurope PMCScholia
Matsubayashi Y, Fukuda M, Nishida E.; ''Evidence for existence of a nuclear pore complex-mediated, cytosol-independent pathway of nuclear translocation of ERK MAP kinase in permeabilized cells.''; PubMedEurope PMCScholia
Lenormand P, Sardet C, Pagès G, L'Allemain G, Brunet A, Pouysségur J.; ''Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts.''; PubMedEurope PMCScholia
Chou FL, Hill JM, Hsieh JC, Pouyssegur J, Brunet A, Glading A, Uberall F, Ramos JW, Werner MH, Ginsberg MH.; ''PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation.''; PubMedEurope PMCScholia
Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O, Baccarini M.; ''A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal.''; PubMedEurope PMCScholia
Casar B, Pinto A, Crespo P.; ''ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task.''; PubMedEurope PMCScholia
Lidke DS, Huang F, Post JN, Rieger B, Wilsbacher J, Thomas JL, Pouysségur J, Jovin TM, Lenormand P.; ''ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation.''; PubMedEurope PMCScholia
Zheng CF, Guan KL.; ''Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.''; PubMedEurope PMCScholia
Burack WR, Shaw AS.; ''Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK.''; PubMedEurope PMCScholia
Bermudez O, Pagès G, Gimond C.; ''The dual-specificity MAP kinase phosphatases: critical roles in development and cancer.''; PubMedEurope PMCScholia
Arthur JS, Ley SC.; ''Mitogen-activated protein kinases in innate immunity.''; PubMedEurope PMCScholia
Casar B, Pinto A, Crespo P.; ''Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes.''; PubMedEurope PMCScholia
Formstecher E, Ramos JW, Fauquet M, Calderwood DA, Hsieh JC, Canton B, Nguyen XT, Barnier JV, Camonis J, Ginsberg MH, Chneiweiss H.; ''PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouysségur J.; ''Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry.''; PubMedEurope PMCScholia
Whitehurst AW, Robinson FL, Moore MS, Cobb MH.; ''The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions.''; PubMedEurope PMCScholia
Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB, Riedl SJ.; ''Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.''; PubMedEurope PMCScholia
Zheng CF, Guan KL.; ''Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues.''; PubMedEurope PMCScholia
Khokhlatchev AV, Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E, Cobb MH.; ''Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation.''; PubMedEurope PMCScholia
Shah OJ, Ghosh S, Hunter T.; ''Mitotic regulation of ribosomal S6 kinase 1 involves Ser/Thr, Pro phosphorylation of consensus and non-consensus sites by Cdc2.''; PubMedEurope PMCScholia
Kondoh K, Nishida E.; ''Regulation of MAP kinases by MAP kinase phosphatases.''; PubMedEurope PMCScholia
Whitehurst AW, Wilsbacher JL, You Y, Luby-Phelps K, Moore MS, Cobb MH.; ''ERK2 enters the nucleus by a carrier-independent mechanism.''; PubMedEurope PMCScholia
Chen RH, Sarnecki C, Blenis J.; ''Nuclear localization and regulation of erk- and rsk-encoded protein kinases.''; PubMedEurope PMCScholia
Adachi M, Fukuda M, Nishida E.; ''Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer.''; PubMedEurope PMCScholia
MAP2K1 (also known as MEK1) phosphorylates the critical Thr202 and Tyr204 on MAPK3 (ERK1), converting two ATP to ADP. Phosphorylation of MAPK3 activates its kinase activity.
MAP2K1 activation requires the phosphorylation of two serine residues (S218 and S222) in the activation loop.
At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'MEK1' are present. At the end of this reaction, 1 molecule of 'phospho_MEK1', and 2 molecules of 'ADP' are present. This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'(Shah et al.2003 ).
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).
After phosphorylation by MAP2Ks, a proportion of activated MAPK translocates into the nucleus where it activates nuclear targets (reviewed in Roskoski, 2012b). MAPKs, which lack a nuclear localization signal (NLS), may 'piggyback' into the nucleus in complex with other nuclear-targeted proteins or may translocate by virtue of interaction with components of the nuclear pore complex (Brunet et al, 1999; Adachi et al, 1999; Matsubayashi et al, 2001; Whitehurst et al, 2002; Khokhlatchev et al, 1998; reviewed in Roskoski, 2012b). Although dimerization of MAPKs was thought to be critical for nuclear translocation, a number of studies have now challenged the physiological relevance of MAPK dimerization and this remains an area of uncertainty (Lenormand et al, 1993; Chen et al, 1992; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Casar et al, 2009; Roskoski, 2012b)
PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus (Formstecher et al, 2001; Whitehurst et al, 2004; Hill et al, 2002; Chou et al, 2003). PEA15 also protects phosphorylated MAPKs in the cytoplasm from inactivating dephosphorylation (Mace et al, 2013). In this way, binding of PEA15 promotes phosphorylation of cytoplasmic MAPK targets at the expense of nuclear ones.
MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Class 1 DUSPs, including DUSP 1, 2, 4 and 5 are nuclear and are generally activated by the same extracellular stimuli that promote MAPK signaling, establishing a negative feedback loop. DUSP5 is specific for MAPK3 and 1, while the other class 1 enzymes have broad specificity. Nuclear MAPKs may also be inactivated by nuclear forms of class III DUSPs, including DUSP8, 10 and 16, although the preferred substrate of these enzymes are the p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kondoh and Nishida, 2007).
MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9, but may also be dephosphorylated by cytosolic forms of class III DUSPs 8, 10 and 16, which preferentially dephosphorylate p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kandoh and Nishida, 2007).
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phosphorylated hexameric IL-6 receptor:Activated
JAKs:p-Y546,Y584-PTPN11Annotated Interactions
phosphorylated hexameric IL-6 receptor:Activated
JAKs:p-Y546,Y584-PTPN11phosphorylated hexameric IL-6 receptor:Activated
JAKs:p-Y546,Y584-PTPN11MAP2K1 activation requires the phosphorylation of two serine residues (S218 and S222) in the activation loop.
This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'(Shah et al.2003 ).
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).