MAPK targets/ Nuclear events mediated by MAP kinases (Homo sapiens)

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3, 8, 94135, 182, 161247, 1419, 201522216, 11, 17, 21410nucleoplasmcytosolPPP2CB p-T325,T331,S362,S374-FOSADPp-T202,Y204-MAPK3 p-T185,Y187-MAPK1 ATF2MEF2C Ribosomal protein S6kinasep-4S,T231,T365-RPS6KA3 p-2S-cJUN:p-2T-ATF2ATPADPp-MAPK8,9,10DUSP3 ATPVRK3:DUSP3FOSp-T69,T71-ATF2 MAPK1 p-MAPK8,9,10 DUSP6 p-T180,Y182-MAPK14 ERK-specific DUSPp-T183,Y185-MAPK9 p-S63-ATF1p-T202,Y204-MAPK3 p-S63,S73-JUN p-S396-MEF2C PPP2CA p-T221,Y223-MAPK10 VRK3 PPP2R1B p-MAPK3/MAPK1/MAPK7dimersp-S212,S360,S376,T581-RPS6KA5p-T325,T331,S362,S374-FOS MAPK7 p-T185,Y187-MAPK1 p-T69,T71-ATF2PPP2R1A RPS6KA5MAPK3/MAPK1/MAPK7dimersPhospho-Ribosomalprotein S6 kinaseELK1PPP2R5D MEF2A p-S63,S73-JUNCREB1p-T180,Y182-MAPK11 MEF2ATF1ADPDUSP7 p-p38 MAPKalpha/betap-T,Y MAPK dimersMAPK3 DUSP4 H2OATPATPActivated MAPKkinases ERK1/2,JNK, p38ATPJUNp-T218,Y220-MAPK7p-T222,S272-MAPKAPK2p-T218,Y220-MAPK7 p-4S,T356,T570-RPS6KA2 p-MEF2Pip-4S,T359,T573-RPS6KA1 ADPADPp-T185,Y187-MAPK1 DUSP3 p-S63,S73-JUN p-S133-CREB1p-p38 MAPK alpha/beta RPS6KA1 p-S408-MEF2A p-T,Y-MAPK8 ADPp-T202,Y204-MAPK3 RPS6KA2 RPS6KA3 ATPATPADPp-4S,T336-ELK1p-2S-cJUN:p-2S,2T-cFOSPP2A-ABdeltaCcomplex


MAPKs are protein kinases that, once activated, phosphorylate their specific cytosolic or nuclear substrates at serine and/or threonine residues. Such phosphorylation events can either positively or negatively regulate substrate, and thus entire signaling cascade activity.

The major cytosolic target of activated ERKs are RSKs (90 kDa Ribosomal protein S6 Kinase). Active RSKs translocates to the nucleus and phosphorylates such factors as c-Fos(on Ser362), SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP Response Element-Binding protein) at Ser133. In the nucleus activated ERKs phosphorylate many other targets such as MSKs (Mitogen- and Stress-activated protein kinases), MNK (MAP interacting kinase) and Elk1 (on Serine383 and Serine389). ERK can directly phosphorylate CREB and also AP-1 components c-Jun and c-Fos. Another important target of ERK is NF-KappaB. Recent studies reveals that nuclear pore proteins are direct substrates for ERK (Kosako H et al, 2009). Other ERK nuclear targets include c-Myc, HSF1 (Heat-Shock Factor-1), STAT1/3 (Signal Transducer and Activator of Transcription-1/3), and many more transcription factors.

Activated p38 MAPK is able to phosphorylate a variety of substrates, including transcription factors STAT1, p53, ATF2 (Activating transcription factor 2), MEF2 (Myocyte enhancer factor-2), protein kinases MSK1, MNK, MAPKAPK2/3, death/survival molecules (Bcl2, caspases), and cell cycle control factors (cyclin D1).

JNK, once activated, phosphorylates a range of nuclear substrates, including transcription factors Jun, ATF, Elk1, p53, STAT1/3 and many other factors. JNK has also been shown to directly phosphorylate many nuclear hormone receptors. For example, peroxisome proliferator-activated receptor 1 (PPAR-1) and retinoic acid receptors RXR and RAR are substrates for JNK. Other JNK targets are heterogeneous nuclear ribonucleoprotein K (hnRNP-K) and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Other adaptor and scaffold proteins have also been characterized as nonnuclear substrates of JNK. View original pathway at Reactome.</div>


Pathway is converted from Reactome ID: 450282
Reactome version: 74
Reactome Author 
Reactome Author: Shamovsky, Veronica

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  1. De Cesare D, Jacquot S, Hanauer A, Sassone-Corsi P.; ''Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene.''; PubMed Europe PMC Scholia
  2. Ainbinder E, Bergelson S, Pinkus R, Daniel V.; ''Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents.''; PubMed Europe PMC Scholia
  3. Yoon S, Seger R.; ''The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.''; PubMed Europe PMC Scholia
  4. Deak M, Clifton AD, Lucocq LM, Alessi DR.; ''Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.''; PubMed Europe PMC Scholia
  5. Okazaki K, Sagata N.; ''The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells.''; PubMed Europe PMC Scholia
  6. Treisman R.; ''Journey to the surface of the cell: Fos regulation and the SRE.''; PubMed Europe PMC Scholia
  7. Dennler S, Prunier C, Ferrand N, Gauthier JM, Atfi A.; ''c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.''; PubMed Europe PMC Scholia
  8. Johnson GL, Lapadat R.; ''Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.''; PubMed Europe PMC Scholia
  9. Bogoyevitch MA, Kobe B.; ''Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases.''; PubMed Europe PMC Scholia
  10. Letourneux C, Rocher G, Porteu F.; ''B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK.''; PubMed Europe PMC Scholia
  11. Marais R, Wynne J, Treisman R.; ''The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain.''; PubMed Europe PMC Scholia
  12. Gupta P, Prywes R.; ''ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression.''; PubMed Europe PMC Scholia
  13. Martín-Blanco E.; ''p38 MAPK signalling cascades: ancient roles and new functions.''; PubMed Europe PMC Scholia
  14. Raivich G.; ''c-Jun expression, activation and function in neural cell death, inflammation and repair.''; PubMed Europe PMC Scholia
  15. Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, Tarcic G, Siwak D, Lahad J, Jacob-Hirsch J, Amariglio N, Vaisman N, Segal E, Rechavi G, Alon U, Mills GB, Domany E, Yarden Y.; ''A module of negative feedback regulators defines growth factor signaling.''; PubMed Europe PMC Scholia
  16. Glover JN, Harrison SC.; ''Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA.''; PubMed Europe PMC Scholia
  17. Duan R, Xie W, Burghardt RC, Safe S.; ''Estrogen receptor-mediated activation of the serum response element in MCF-7 cells through MAPK-dependent phosphorylation of Elk-1.''; PubMed Europe PMC Scholia
  18. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.; ''Molecular interpretation of ERK signal duration by immediate early gene products.''; PubMed Europe PMC Scholia
  19. Ranganathan A, Pearson GW, Chrestensen CA, Sturgill TW, Cobb MH.; ''The MAP kinase ERK5 binds to and phosphorylates p90 RSK.''; PubMed Europe PMC Scholia
  20. Roux PP, Richards SA, Blenis J.; ''Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.''; PubMed Europe PMC Scholia
  21. Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE.; ''ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation.''; PubMed Europe PMC Scholia
  22. Bonni A, Ginty DD, Dudek H, Greenberg ME.; ''Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals.''; PubMed Europe PMC Scholia


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113260view11:32, 2 November 2020ReactomeTeamReactome version 74
112475view15:42, 9 October 2020ReactomeTeamReactome version 73
101386view11:27, 1 November 2018ReactomeTeamreactome version 66
100924view21:03, 31 October 2018ReactomeTeamreactome version 65
100464view19:37, 31 October 2018ReactomeTeamreactome version 64
100010view16:21, 31 October 2018ReactomeTeamreactome version 63
99563view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93906view13:44, 16 August 2017ReactomeTeamreactome version 61
93480view11:24, 9 August 2017ReactomeTeamreactome version 61
86577view09:21, 11 July 2016ReactomeTeamreactome version 56
83294view10:40, 18 November 2015ReactomeTeamVersion54
81428view12:57, 21 August 2015ReactomeTeamVersion53
76899view08:17, 17 July 2014ReactomeTeamFixed remaining interactions
76604view11:58, 16 July 2014ReactomeTeamFixed remaining interactions
75935view09:59, 11 June 2014ReactomeTeamRe-fixing comment source
75637view10:52, 10 June 2014ReactomeTeamReactome 48 Update
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74636view08:41, 30 April 2014ReactomeTeamReactome46
44891view10:15, 6 October 2011MartijnVanIerselOntology Term : 'MAPK signaling pathway' added !
42063view21:54, 4 March 2011MaintBotAutomatic update
39871view05:54, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATF1ProteinP18846 (Uniprot-TrEMBL)
ATF2ProteinP15336 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activated MAPK

kinases ERK1/2,

JNK, p38
ComplexR-HSA-450307 (Reactome)
CREB1ProteinP16220 (Uniprot-TrEMBL)
DUSP3 ProteinP51452 (Uniprot-TrEMBL)
DUSP4 ProteinQ13115 (Uniprot-TrEMBL)
DUSP6 ProteinQ16828 (Uniprot-TrEMBL)
DUSP7 ProteinQ16829 (Uniprot-TrEMBL)
ELK1ProteinP19419 (Uniprot-TrEMBL)
ERK-specific DUSPComplexR-HSA-203792 (Reactome)
FOSProteinP01100 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
JUNProteinP05412 (Uniprot-TrEMBL)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPK3/MAPK1/MAPK7 dimersComplexR-HSA-199955 (Reactome)
MAPK7 ProteinQ13164 (Uniprot-TrEMBL)
MEF2A ProteinQ02078 (Uniprot-TrEMBL)
MEF2C ProteinQ06413 (Uniprot-TrEMBL)
MEF2ComplexR-HSA-199911 (Reactome)
PP2A-ABdeltaC complexComplexR-HSA-165970 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
Phospho-Ribosomal protein S6 kinaseComplexR-HSA-199849 (Reactome)
PiMetaboliteCHEBI:43474 (ChEBI)
RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
Ribosomal protein S6 kinaseComplexR-HSA-199858 (Reactome)
VRK3 ProteinQ8IV63 (Uniprot-TrEMBL)
VRK3:DUSP3ComplexR-HSA-8942511 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSComplexR-HSA-450327 (Reactome)
p-2S-cJUN:p-2T-ATF2ComplexR-HSA-450262 (Reactome)
p-4S,T231,T365-RPS6KA3 ProteinP51812 (Uniprot-TrEMBL)
p-4S,T336-ELK1ProteinP19419 (Uniprot-TrEMBL)
p-4S,T356,T570-RPS6KA2 ProteinQ15349 (Uniprot-TrEMBL)
p-4S,T359,T573-RPS6KA1 ProteinQ15418 (Uniprot-TrEMBL)
p-MAPK3/MAPK1/MAPK7 dimersComplexR-HSA-199878 (Reactome)
p-MAPK8,9,10 R-HSA-450253 (Reactome)
p-MAPK8,9,10ComplexR-HSA-450253 (Reactome)
p-MEF2ComplexR-HSA-199933 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S212,S360,S376,T581-RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
p-S396-MEF2C ProteinQ06413 (Uniprot-TrEMBL)
p-S408-MEF2A ProteinQ02078 (Uniprot-TrEMBL)
p-S63,S73-JUN ProteinP05412 (Uniprot-TrEMBL)
p-S63,S73-JUNProteinP05412 (Uniprot-TrEMBL)
p-S63-ATF1ProteinP18846 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T,Y-MAPK8 ProteinP45983 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T183,Y185-MAPK9 ProteinP45984 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T218,Y220-MAPK7 ProteinQ13164 (Uniprot-TrEMBL)
p-T218,Y220-MAPK7ProteinQ13164 (Uniprot-TrEMBL)
p-T221,Y223-MAPK10 ProteinP53779 (Uniprot-TrEMBL)
p-T222,S272-MAPKAPK2ProteinP49137 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOSProteinP01100 (Uniprot-TrEMBL)
p-T69,T71-ATF2 ProteinP15336 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
p-p38 MAPK alpha/betaComplexR-HSA-198703 (Reactome)
p-p38 MAPK alpha/beta R-HSA-198703 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-168053 (Reactome)
ADPArrowR-HSA-168136 (Reactome)
ADPArrowR-HSA-198669 (Reactome)
ADPArrowR-HSA-198731 (Reactome)
ADPArrowR-HSA-198746 (Reactome)
ADPArrowR-HSA-198756 (Reactome)
ADPArrowR-HSA-199895 (Reactome)
ADPArrowR-HSA-199910 (Reactome)
ADPArrowR-HSA-199917 (Reactome)
ADPArrowR-HSA-199929 (Reactome)
ADPArrowR-HSA-199935 (Reactome)
ADPArrowR-HSA-450325 (Reactome)
ATF1R-HSA-199910 (Reactome)
ATF2R-HSA-168053 (Reactome)
ATPR-HSA-168053 (Reactome)
ATPR-HSA-168136 (Reactome)
ATPR-HSA-198669 (Reactome)
ATPR-HSA-198731 (Reactome)
ATPR-HSA-198746 (Reactome)
ATPR-HSA-198756 (Reactome)
ATPR-HSA-199895 (Reactome)
ATPR-HSA-199910 (Reactome)
ATPR-HSA-199917 (Reactome)
ATPR-HSA-199929 (Reactome)
ATPR-HSA-199935 (Reactome)
ATPR-HSA-450325 (Reactome)
Activated MAPK

kinases ERK1/2,

JNK, p38
mim-catalysisR-HSA-168053 (Reactome)
CREB1R-HSA-199895 (Reactome)
CREB1R-HSA-199917 (Reactome)
CREB1R-HSA-199935 (Reactome)
ELK1R-HSA-198731 (Reactome)
ERK-specific DUSPmim-catalysisR-HSA-203797 (Reactome)
FOSR-HSA-450325 (Reactome)
H2OR-HSA-199959 (Reactome)
H2OR-HSA-203797 (Reactome)
JUNR-HSA-168136 (Reactome)
MAPK3/MAPK1/MAPK7 dimersArrowR-HSA-199959 (Reactome)
MAPK3/MAPK1/MAPK7 dimersArrowR-HSA-203797 (Reactome)
MEF2R-HSA-199929 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-199959 (Reactome)
Phospho-Ribosomal protein S6 kinaseArrowR-HSA-198746 (Reactome)
Phospho-Ribosomal protein S6 kinasemim-catalysisR-HSA-199895 (Reactome)
PiArrowR-HSA-199959 (Reactome)
PiArrowR-HSA-203797 (Reactome)
R-HSA-168053 (Reactome) the Raf–MEK–ERK pathway induces phosphorylation of ATF2 Thr71, whereas subsequent ATF2 Thr69 phosphorylation requires the Ral–RalGDS–Src–p38 pathway. Cooperation between ERK and p38 was found to be essential for ATF2 activation by these mitogens; the activity of p38 and JNK/SAPK in growth factor-stimulated fibroblasts is insufficient to phosphorylate ATF2 Thr71 or Thr69 + 71 significantly by themselves, while ERK cannot dual phosphorylate ATF2 Thr69 + 71 efficiently.
R-HSA-168136 (Reactome) JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.
R-HSA-168440 (Reactome) At the beginning of this reaction, 1 molecule of 'c-Jun-P', and 1 molecule of 'ATF-2-P' are present. At the end of this reaction, 1 molecule of 'AP-1' is present.

R-HSA-198669 (Reactome) MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.

R-HSA-198731 (Reactome) Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon stimulation with growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like FOS (c-fos) (Marais et al, 1993; Gille et al, 1995; Duan et al, 1998; reviewed in Treisman, 1995).
R-HSA-198746 (Reactome) The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.
RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.
Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

R-HSA-198756 (Reactome) MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues.
R-HSA-199895 (Reactome) CREB is phosphorylated at Serine 133 by RSK1/2/3.
R-HSA-199910 (Reactome) Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.
R-HSA-199917 (Reactome) p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.
R-HSA-199929 (Reactome) The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum.
R-HSA-199935 (Reactome) MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).
R-HSA-199959 (Reactome) ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK.
Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown.
R-HSA-203797 (Reactome) Over 10 dual specificity phosphatases (DUSPs) active on MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity.
R-HSA-450292 (Reactome) The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).
R-HSA-450325 (Reactome) The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity.

On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.

Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.

RPS6KA5R-HSA-198669 (Reactome)
RPS6KA5R-HSA-198756 (Reactome)
Ribosomal protein S6 kinaseR-HSA-198746 (Reactome)
VRK3:DUSP3TBarR-HSA-203797 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSArrowR-HSA-450292 (Reactome)
p-2S-cJUN:p-2T-ATF2ArrowR-HSA-168440 (Reactome)
p-4S,T336-ELK1ArrowR-HSA-198731 (Reactome)
p-MAPK3/MAPK1/MAPK7 dimersR-HSA-199959 (Reactome)
p-MAPK3/MAPK1/MAPK7 dimersR-HSA-203797 (Reactome)
p-MAPK3/MAPK1/MAPK7 dimersmim-catalysisR-HSA-198746 (Reactome)
p-MAPK8,9,10mim-catalysisR-HSA-168136 (Reactome)
p-MEF2ArrowR-HSA-199929 (Reactome)
p-S133-CREB1ArrowR-HSA-199895 (Reactome)
p-S133-CREB1ArrowR-HSA-199917 (Reactome)
p-S133-CREB1ArrowR-HSA-199935 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowR-HSA-198669 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowR-HSA-198756 (Reactome)
p-S212,S360,S376,T581-RPS6KA5mim-catalysisR-HSA-199910 (Reactome)
p-S212,S360,S376,T581-RPS6KA5mim-catalysisR-HSA-199935 (Reactome)
p-S63,S73-JUNArrowR-HSA-168136 (Reactome)
p-S63,S73-JUNR-HSA-168440 (Reactome)
p-S63,S73-JUNR-HSA-450292 (Reactome)
p-S63-ATF1ArrowR-HSA-199910 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-198731 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-198756 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-450325 (Reactome)
p-T218,Y220-MAPK7mim-catalysisR-HSA-199929 (Reactome)
p-T222,S272-MAPKAPK2mim-catalysisR-HSA-199917 (Reactome)
p-T325,T331,S362,S374-FOSArrowR-HSA-450325 (Reactome)
p-T325,T331,S362,S374-FOSR-HSA-450292 (Reactome)
p-T69,T71-ATF2ArrowR-HSA-168053 (Reactome)
p-T69,T71-ATF2R-HSA-168440 (Reactome)
p-p38 MAPK alpha/betamim-catalysisR-HSA-198669 (Reactome)

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