RAF-independent MAPK1/3 activation (Homo sapiens)

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12, 21, 2311, 15, 231, 12, 20191, 203, 4, 10, 14, 17...202-4, 10, 14...92065, 7, 13, 2411, 15, 23nucleoplasmcytosolADPADPp-T286,T292-MAP2K1 p-S218,S222,T286,T292-MAP2K1 p-T,Y MAPK dimers p-T202,Y204-MAPK3 p-T,Y MAPKs PEA15p-S218,S222-MAP2K1 p-Y546,Y584-PTPN11 MAPK3 p-T,Y MAPK dimers p-S,T-MAP2K2 MAPKs MAPK3 MAPK monomers anddimersp-S,T-MAP2K2:p-T,Y-MAPK1p-T185,Y187-MAPK1 MAPK3p-Y1007-JAK2 p-T,Y MAPK dimers p-S,T-MAP2K2p-S218,S222-MAP2K1 p-T,Y MAPK monomersand dimersPip-T,Y MAPK monomersand dimers:PEA15p-T,Y MAPK dimersADPp-2S-MAP2K1:MAPK3p-T161-CDK1ATPMAP2K1 H2Op-T185,Y187-MAPK1MAPK1 H2Op-T,Y MAPK monomersand dimersPip-T202,Y204-MAPK3 MAPK1 p-S218,S222-MAP2K1ATPIL6R p-S,T-MAP2K2 p-S218,S222-MAP2K1 IL6R-2 IL6 MAPK1p-T,Y-MAPK3:p-2S-MAP2K1p-T,Y MAPKsMAP2K1MAPK3 ATPp-T,Y MAPKs p-2T-MAP2K1p-T185,Y187-MAPK1 MAPK monomers anddimersp-S,T-MAP2K2:MAPK1p-Y1054-TYK2 p-T,Y MAPKs MAP3K8(TPL2)-dependentMAPK1/3 activationIL6:TyrosinephosphorylatedhexamericIL-6receptor:ActivatedJAKs:p-Y546,Y584-PTPN11p-5Y-IL6ST-1 p-T185,Y187-MAPK1 p-T202,Y204-MAPK3 MAPK1 p-T202,Y204-MAPK3p-Y1034-JAK1 PEA15 8, 21


Description

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>

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Reactome-Converter 
Pathway is converted from Reactome ID: 112409
Reactome-version 
Reactome version: 61

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Bibliography

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  1. 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.''; PubMed Europe PMC
  2. Chen RH, Sarnecki C, Blenis J.; ''Nuclear localization and regulation of erk- and rsk-encoded protein kinases.''; PubMed Europe PMC
  3. 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.''; PubMed Europe PMC
  4. 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.''; PubMed Europe PMC
  5. 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.''; PubMed Europe PMC
  6. Kondoh K, Nishida E.; ''Regulation of MAP kinases by MAP kinase phosphatases.''; PubMed Europe PMC
  7. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC
  8. Burack WR, Shaw AS.; ''Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK.''; PubMed Europe PMC
  9. Bermudez O, Pagès G, Gimond C.; ''The dual-specificity MAP kinase phosphatases: critical roles in development and cancer.''; PubMed Europe PMC
  10. Whitehurst AW, Wilsbacher JL, You Y, Luby-Phelps K, Moore MS, Cobb MH.; ''ERK2 enters the nucleus by a carrier-independent mechanism.''; PubMed Europe PMC
  11. 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.''; PubMed Europe PMC
  12. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC
  13. Zheng CF, Guan KL.; ''Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues.''; PubMed Europe PMC
  14. Casar B, Pinto A, Crespo P.; ''ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task.''; PubMed Europe PMC
  15. 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.''; PubMed Europe PMC
  16. Whitehurst AW, Robinson FL, Moore MS, Cobb MH.; ''The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions.''; PubMed Europe PMC
  17. 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.''; PubMed Europe PMC
  18. Casar B, Pinto A, Crespo P.; ''Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes.''; PubMed Europe PMC
  19. 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.''; PubMed Europe PMC
  20. Arthur JS, Ley SC.; ''Mitogen-activated protein kinases in innate immunity.''; PubMed Europe PMC
  21. 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.''; PubMed Europe PMC
  22. 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.''; PubMed Europe PMC
  23. Gantke T, Sriskantharajah S, Ley SC.; ''Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase.''; PubMed Europe PMC
  24. 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.''; PubMed Europe PMC
  25. Zheng CF, Guan KL.; ''Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101608view11:47, 1 November 2018ReactomeTeamreactome version 66
101145view21:33, 31 October 2018ReactomeTeamreactome version 65
100673view20:06, 31 October 2018ReactomeTeamreactome version 64
100223view16:51, 31 October 2018ReactomeTeamreactome version 63
99774view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93952view13:47, 16 August 2017ReactomeTeamreactome version 61
93547view11:26, 9 August 2017ReactomeTeamreactome version 61
88125view10:14, 26 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
88124view10:13, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86646view09:23, 11 July 2016ReactomeTeamreactome version 56
83296view10:40, 18 November 2015ReactomeTeamVersion54
81433view12:57, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
IL6 ProteinP05231 (Uniprot-TrEMBL)
IL6:Tyrosine

phosphorylated hexameric IL-6 receptor:Activated

JAKs:p-Y546,Y584-PTPN11
ComplexR-HSA-1112753 (Reactome)
IL6R ProteinP08887 (Uniprot-TrEMBL)
IL6R-2 ProteinP08887-2 (Uniprot-TrEMBL)
MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
MAP2K1ComplexR-HSA-112336 (Reactome)
MAP3K8

(TPL2)-dependent

MAPK1/3 activation
PathwayR-HSA-5684264 (Reactome) Tumor progression locus-2 (TPL2, also known as COT and MAP3K8) functions as a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) in various stress-responsive signaling cascades. MAP3K8 (TPL2) mediates phosphorylation of MAP2Ks (MEK1/2) which in turn phosphorylate MAPK (ERK1/2) (Gantke T et al., 2011).

In the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.

MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).

MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).

MAPK monomers and dimersComplexR-HSA-5675361 (Reactome)
MAPK monomers and dimersComplexR-HSA-5675363 (Reactome)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK1ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPK3ProteinP27361 (Uniprot-TrEMBL)
MAPKs R-HSA-169291 (Reactome)
PEA15 ProteinQ15121 (Uniprot-TrEMBL)
PEA15ProteinQ15121 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
p-2S-MAP2K1:MAPK3ComplexR-HSA-109838 (Reactome)
p-2T-MAP2K1ComplexR-HSA-112340 (Reactome)
p-5Y-IL6ST-1 ProteinP40189-1 (Uniprot-TrEMBL)
p-S,T-MAP2K2 ProteinP36507 (Uniprot-TrEMBL)
p-S,T-MAP2K2:MAPK1ComplexR-HSA-109849 (Reactome)
p-S,T-MAP2K2:p-T,Y-MAPK1ComplexR-HSA-109854 (Reactome)
p-S,T-MAP2K2ProteinP36507 (Uniprot-TrEMBL)
p-S218,S222,T286,T292-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1ProteinQ02750 (Uniprot-TrEMBL)
p-T,Y MAPK dimers R-HSA-1268261 (Reactome)
p-T,Y MAPK dimers R-HSA-198701 (Reactome)
p-T,Y MAPK dimersComplexR-HSA-1268261 (Reactome)
p-T,Y MAPK monomers and dimers:PEA15ComplexR-HSA-5675205 (Reactome)
p-T,Y MAPK monomers and dimersComplexR-HSA-5674340 (Reactome)
p-T,Y MAPK monomers and dimersComplexR-HSA-5674341 (Reactome)
p-T,Y MAPKs R-HSA-169289 (Reactome)
p-T,Y MAPKs R-HSA-5674338 (Reactome)
p-T,Y MAPKsComplexR-HSA-169289 (Reactome)
p-T,Y-MAPK3:p-2S-MAP2K1ComplexR-HSA-109843 (Reactome)
p-T161-CDK1ProteinP06493 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3ProteinP27361 (Uniprot-TrEMBL)
p-T286,T292-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y1034-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y1054-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 ProteinQ06124 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-109860 (Reactome)
ADPArrowR-HSA-109862 (Reactome)
ADPArrowR-HSA-112342 (Reactome)
ATPR-HSA-109860 (Reactome)
ATPR-HSA-109862 (Reactome)
ATPR-HSA-112342 (Reactome)
H2OR-HSA-5675373 (Reactome)
H2OR-HSA-5675376 (Reactome)
IL6:Tyrosine

phosphorylated hexameric IL-6 receptor:Activated

JAKs:p-Y546,Y584-PTPN11
ArrowR-HSA-109857 (Reactome)
IL6:Tyrosine

phosphorylated hexameric IL-6 receptor:Activated

JAKs:p-Y546,Y584-PTPN11
ArrowR-HSA-109858 (Reactome)
MAP2K1R-HSA-112342 (Reactome)
MAPK monomers and dimersArrowR-HSA-5675373 (Reactome)
MAPK monomers and dimersArrowR-HSA-5675376 (Reactome)
MAPK1R-HSA-109858 (Reactome)
MAPK3R-HSA-109857 (Reactome)
PEA15R-HSA-5675206 (Reactome)
PiArrowR-HSA-5675373 (Reactome)
PiArrowR-HSA-5675376 (Reactome)
R-HSA-109857 (Reactome) In the cytoplasm phosphorylated MAP2K1 (MEK1) may encounter monomeric, inactive MAPK3 (ERK1).
R-HSA-109858 (Reactome) In the cytoplasm phosphorylated MAP2K2 (MEK2) may encounter monomeric, inactive MAPK1 (ERK2).
R-HSA-109860 (Reactome) 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.

R-HSA-109862 (Reactome) MAP2K2 (MEK2) phosphorylates MAPK1 (ERK2). Phosphorylation of MAPK1 activates its kinase activity.
R-HSA-109863 (Reactome) MAP2K1 (MEK1) dissociates from phosphorylated MAPK3 (ERK1), allowing the dimerization of p-S202,204-MAP2K.
R-HSA-109864 (Reactome) MAP2K2 (MEK2) dissociates from phosphorylated MAPK1 (ERK2), allowing activated MAPK1 (ERK2) to dimerise (Zheng and Guang 1994).
R-HSA-112342 (Reactome) 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 ).
R-HSA-5674385 (Reactome) 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).
R-HSA-5674387 (Reactome) 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)
R-HSA-5675206 (Reactome) 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.
R-HSA-5675373 (Reactome) 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).
R-HSA-5675376 (Reactome) 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).
p-2S-MAP2K1:MAPK3ArrowR-HSA-109857 (Reactome)
p-2S-MAP2K1:MAPK3R-HSA-109860 (Reactome)
p-2S-MAP2K1:MAPK3mim-catalysisR-HSA-109860 (Reactome)
p-2T-MAP2K1ArrowR-HSA-112342 (Reactome)
p-2T-MAP2K1TBarR-HSA-109860 (Reactome)
p-S,T-MAP2K2:MAPK1ArrowR-HSA-109858 (Reactome)
p-S,T-MAP2K2:MAPK1R-HSA-109862 (Reactome)
p-S,T-MAP2K2:MAPK1mim-catalysisR-HSA-109862 (Reactome)
p-S,T-MAP2K2:p-T,Y-MAPK1ArrowR-HSA-109862 (Reactome)
p-S,T-MAP2K2:p-T,Y-MAPK1R-HSA-109864 (Reactome)
p-S,T-MAP2K2ArrowR-HSA-109864 (Reactome)
p-S,T-MAP2K2R-HSA-109858 (Reactome)
p-S218,S222-MAP2K1ArrowR-HSA-109863 (Reactome)
p-S218,S222-MAP2K1R-HSA-109857 (Reactome)
p-T,Y MAPK dimersArrowR-HSA-5674385 (Reactome)
p-T,Y MAPK monomers and dimers:PEA15ArrowR-HSA-5675206 (Reactome)
p-T,Y MAPK monomers and dimersArrowR-HSA-5674387 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5674387 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5675206 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5675373 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5675376 (Reactome)
p-T,Y MAPKsR-HSA-5674385 (Reactome)
p-T,Y-MAPK3:p-2S-MAP2K1ArrowR-HSA-109860 (Reactome)
p-T,Y-MAPK3:p-2S-MAP2K1R-HSA-109863 (Reactome)
p-T161-CDK1mim-catalysisR-HSA-112342 (Reactome)
p-T185,Y187-MAPK1ArrowR-HSA-109864 (Reactome)
p-T202,Y204-MAPK3ArrowR-HSA-109863 (Reactome)

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