RAF-independent MAPK1/3 activation (Homo sapiens)

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5, 12, 136, 11, 15, 2012, 14, 161, 8-10, 13...2, 13, 21161614, 162, 13, 211, 3, 7-10, 13...cytosolnucleoplasmMAPK monomers anddimersp-5Y-IL6ST-1 p-Y546,Y584-PTPN11 p-S,T-MAP2K2:MAPK1MAPK3 p-T,Y-MAPK3:p-2S-MAP2K1p-S,T-MAP2K2 p-S218,S222-MAP2K1 MAPK1 MAPK1p-2S-MAP2K1:MAPK3IL6R IL6 ADPATPPEA15H2Op-T,Y MAPKsp-T202,Y204-MAPK3ATPADPp-T,Y MAPK monomersand dimersp-T,Y MAPK monomersand dimers:PEA15p-S,T-MAP2K2 Pip-S,T-MAP2K2ATPPEA15 p-T185,Y187-MAPK1PiMAP2K1MAPK3p-T,Y MAPK dimersp-T161-CDK1p-T202,Y204-MAPK3 p-S218,S222-MAP2K1H2Op-T202,Y204-MAPK3 p-T185,Y187-MAPK1 p-T185,Y187-MAPK1 ADPInterleukin-1signalingp-2T-MAP2K1p-S218,S222-MAP2K1 MAPK monomers anddimersIL6R-2 p-S,T-MAP2K2:p-T,Y-MAPK1p-T,Y MAPK monomersand dimersIL6:Tyrosinephosphorylatedhexameric IL-6receptor:ActivatedJAKs:p-SHP24, 18


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). Source:Reactome.</div>

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

phosphorylated hexameric IL-6 receptor:Activated

JAKs:p-SHP2		ComplexR-HSA-1112753 (Reactome)
IL6R ProteinP08887 (Uniprot-TrEMBL)
IL6R-2 ProteinP08887-2 (Uniprot-TrEMBL)
Interleukin-1 signalingPathwayR-HSA-446652 (Reactome) Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).

TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear.
MAP2K1R-HSA-112336 (Reactome)
MAPK monomers and dimersR-HSA-5675361 (Reactome)
MAPK monomers and dimersR-HSA-5675363 (Reactome)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK1ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPK3ProteinP27361 (Uniprot-TrEMBL)
PEA15 ProteinQ15121 (Uniprot-TrEMBL)
PEA15ProteinQ15121 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
p-2S-MAP2K1:MAPK3ComplexR-HSA-109838 (Reactome)
p-2T-MAP2K1R-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-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1ProteinQ02750 (Uniprot-TrEMBL)
p-T,Y MAPK dimersR-HSA-1268261 (Reactome)
p-T,Y MAPK monomers and dimers:PEA15ComplexR-HSA-5675205 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5674340 (Reactome)
p-T,Y MAPK monomers and dimersR-HSA-5674341 (Reactome)
p-T,Y MAPKsR-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-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-SHP2		ArrowR-HSA-109857 (Reactome)
IL6:Tyrosine

phosphorylated hexameric IL-6 receptor:Activated

JAKs:p-SHP2		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.
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)'.

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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