RAF-independent MAPK1/3 activation (Homo sapiens)

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4, 9, 161, 4, 832, 5, 954, 6, 7, 10-13, 19...14, 15, 18, 22174, 7, 10, 12, 13, 19...2, 51, 4, 8245cytosolnucleoplasmp-S,T-MAP2K2 DUSP2 p-T,Y MAPK dimers MAPK3 PiPEA15p-T,Y MAPK dimers IL6 p-Y1034-JAK1 H2Op-T185,Y187-MAPK1 p-S,T-MAP2K2:p-T,Y-MAPK1p-T202,Y204-MAPK3 MAPK1 p-T,Y MAPK monomersand dimers:PEA15p-T,Y MAPK dimersIL6:TyrosinephosphorylatedhexamericIL-6receptor:ActivatedJAKs:p-Y546,Y584-PTPN11p-T,Y MAPK monomersand dimersATPp-T286,T292-MAP2K1 p-T185,Y187-MAPK1p-Y1007-JAK2 ADPMAPK1 MAPK3 ADPp-5Y-IL6ST-1 p-T,Y-MAPK3:p-2S-MAP2K1MAPKs DUSP16 ADPp-T202,Y204-MAPK3 p-S218,S222,T286,T292-MAP2K1 IL6R-2 p-T,Y MAPKsATPp-T185,Y187-MAPK1 DUSP7 H2Op-S,T-MAP2K2:MAPK1MAPK1PiMAPK3p-S218,S222-MAP2K1 MAP2K1MAPK1 p-T202,Y204-MAPK3 cytosolic MAPK DUSPsDUSP4 p-S218,S222-MAP2K1 p-Y546,Y584-PTPN11 DUSP8 nuclear MAPK DUSPsp-Y1054-TYK2 p-S,T-MAP2K2 p-T,Y MAPKs p-S218,S222-MAP2K1 MAP2K1 p-T,Y MAPKs p-S,T-MAP2K2DUSP10 DUSP6 p-T,Y MAPKs MAPK monomers anddimersp-2T-MAP2K1p-T,Y MAPK monomersand dimersPEA15 p-T161-CDK1IL6R p-S218,S222-MAP2K1DUSP8 DUSP10 p-2S-MAP2K1:MAPK3DUSP5 DUSP9 MAPK monomers anddimersATPDUSP1 DUSP16 MAPK3 p-T202,Y204-MAPK3p-T,Y MAPK dimers p-T185,Y187-MAPK1


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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Pathway is converted from Reactome ID: 112409
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Reactome version: 74

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Bibliography

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  1. Gantke T, Sriskantharajah S, Ley SC.; ''Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase.''; PubMed Europe PMC Scholia
  2. 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 Scholia
  3. 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 Scholia
  4. 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 Scholia
  5. 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 Scholia
  6. Casar B, Pinto A, Crespo P.; ''ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task.''; PubMed Europe PMC Scholia
  7. 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 Scholia
  8. Zheng CF, Guan KL.; ''Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.''; PubMed Europe PMC Scholia
  9. Burack WR, Shaw AS.; ''Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK.''; PubMed Europe PMC Scholia
  10. Bermudez O, Pagès G, Gimond C.; ''The dual-specificity MAP kinase phosphatases: critical roles in development and cancer.''; PubMed Europe PMC Scholia
  11. Arthur JS, Ley SC.; ''Mitogen-activated protein kinases in innate immunity.''; PubMed Europe PMC Scholia
  12. 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 Scholia
  13. 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 Scholia
  14. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  15. 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 Scholia
  16. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  17. 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 Scholia
  18. 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 Scholia
  19. Zheng CF, Guan KL.; ''Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues.''; PubMed Europe PMC Scholia
  20. 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 Scholia
  21. 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 Scholia
  22. Kondoh K, Nishida E.; ''Regulation of MAP kinases by MAP kinase phosphatases.''; PubMed Europe PMC Scholia
  23. 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 Scholia
  24. Chen RH, Sarnecki C, Blenis J.; ''Nuclear localization and regulation of erk- and rsk-encoded protein kinases.''; PubMed Europe PMC Scholia
  25. 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 Scholia

History

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CompareRevisionActionTimeUserComment
115047view16:59, 25 January 2021ReactomeTeamReactome version 75
113491view11:56, 2 November 2020ReactomeTeamReactome version 74
112691view16:08, 9 October 2020ReactomeTeamReactome version 73
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:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
DUSP1 ProteinP28562 (Uniprot-TrEMBL)
DUSP10 ProteinQ9Y6W6 (Uniprot-TrEMBL)
DUSP16 ProteinQ9BY84 (Uniprot-TrEMBL)
DUSP2 ProteinQ05923 (Uniprot-TrEMBL)
DUSP4 ProteinQ13115 (Uniprot-TrEMBL)
DUSP5 ProteinQ16690 (Uniprot-TrEMBL)
DUSP6 ProteinQ16828 (Uniprot-TrEMBL)
DUSP7 ProteinQ16829 (Uniprot-TrEMBL)
DUSP8 ProteinQ13202 (Uniprot-TrEMBL)
DUSP9 ProteinQ99956 (Uniprot-TrEMBL)
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)
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:43474 (ChEBI)
cytosolic MAPK DUSPsComplexR-HSA-5675365 (Reactome)
nuclear MAPK DUSPsComplexR-HSA-5675368 (Reactome)
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

View all...
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).
cytosolic MAPK DUSPsmim-catalysisR-HSA-5675376 (Reactome)
nuclear MAPK DUSPsmim-catalysisR-HSA-5675373 (Reactome)
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 dimers:PEA15TBarR-HSA-5674387 (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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