Pathway Human Homo sapiens

MAPK6/MAPK4 signaling

R-HSA-5687128 in Reactome release 97: under MAPK family signaling cascades, with 80 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-5687128 (mouse), R-RNO-5687128 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-5687128.5
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2015-06-17
Last updated: 2023-06-07
Events inside: 40, counted from the record

MAPK6 and MAPK4 (also known as ERK3 and ERK4) are vertebrate-specific atypical MAP kinases. Atypical MAPK are less well characterized than their conventional counterparts, and are generally classified as such based on their lack of activation by MAPKK family members. Unlike the conventional MAPK proteins, which contain a Thr-X-Tyr motif in the activation loop, MAPK6 and 4 have a single Ser-Glu-Gly phospho-acceptor motif (reviewed in Coulombe and Meloche, 2007; Cargnello et al, 2011). MAPK6 is also distinct in being an unstable kinase, whose turnover is mediated by ubiquitin-dependent degradation (Coulombe et al, 2003; Coulombe et al, 2004). The biological functions and pathways governing MAPK6 and 4 are not well established. MAPK6 and 4 are phosphorylated downstream of class I p21 activated kinases (PAKs) in a RAC- or CDC42-dependent manner (Deleris et al, 2008; Perander et al, 2008; Deleris et al, 2011; De La Mota-Peynado et al, 2011). One of the only well established substrates of MAPK6 and 4 is MAPKAPK5, which contributes to cell motility by promoting the HSBP1-dependent rearrangement of F-actin (Gerits et al, 2007; Kostenko et al, 2009a; reviewed in Kostenko et al, 2011b). The atypical MAPKs also contribute to cell motility and invasiveness through the NCOA3:ETV4-dependent regulation of MMP gene expression (Long et al, 2012; Yan et al, 2008; Qin et al, 2008). Both of these pathways may be misregulated in human cancers (reviewed in Myant and Sansom, 2011; Kostenko et al, 2012)

Literature Reactome attaches

Atypical mitogen-activated protein kinases: structure, regulation and functionsBiochim. Biophys. Acta, 2007, vol. 1773, p. 1376-87PubMed 17161475
Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinasesMicrobiol. Mol. Biol. Rev., 2011, vol. 75, p. 50-83PubMed 21372320
N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasomeMol. Cell. Biol., 2004, vol. 24, p. 6140-50PubMed 15226418
Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiationMol. Cell. Biol., 2003, vol. 23, p. 4542-58PubMed 12808096
Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5J. Cell. Physiol., 2008, vol. 217, p. 778-88PubMed 18720373
Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathwayJ. Biol. Chem., 2011, vol. 286, p. 6470-8PubMed 21177870
The Ser(186) phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5Biochem. J., 2008, vol. 411, p. 613-22PubMed 18248330
Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5J. Biol. Chem., 2007, vol. 282, p. 37232-43PubMed 17947239
PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5Cell. Signal., 2009, vol. 21, p. 712-8PubMed 19166925
Cross-talk between protein kinase A and the MAPK-activated protein kinases RSK1 and MK5J. Recept. Signal Transduct. Res., 2011, vol. 31, p. 1-9PubMed 20849292
ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasionJ. Clin. Invest., 2012, vol. 122, p. 1869-80PubMed 22505454
The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expressionMol. Cell. Biol., 2008, vol. 28, p. 5937-50PubMed 18644862
Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expressionCancer Res., 2008, vol. 68, p. 5460-8PubMed 18593949
More, more, more: downregulation of a MK5-FoxO3a-mir34b/c pathway further increases c-Myc levels in colorectal cancerMol. Cell, 2011, vol. 41, p. 369-70PubMed 21329875
Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5J Mol Signal, 2012, vol. 7, p. 9PubMed 22800433

Reactome's record lists 14 orthologous events, R-RNO-5687128 (Rattus norvegicus), R-MMU-5687128 (Mus musculus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-05 ET · Reactome pathway browser"MAPK6/MAPK4 signaling". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-5687128 with StableID: R-HSA-5687128.5 (accessed 2026-10-05 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 80 genes in this human pathway; showing 1 to 80, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneADRM1	AuthorityHGNC:15759	Mapping file id11047 NCBI file	EvidenceTAS
GeneAGO1	AuthorityHGNC:3262	Mapping file id26523 NCBI file	EvidenceTAS
GeneAGO2	AuthorityHGNC:3263	Mapping file id27161 NCBI file	EvidenceTAS
GeneAGO3	AuthorityHGNC:18421	Mapping file id192669 NCBI file	EvidenceTAS
GeneAGO4	AuthorityHGNC:18424	Mapping file id192670 NCBI file	EvidenceTAS
GeneCCND3	AuthorityHGNC:1585	Mapping file id896 NCBI file	EvidenceTAS
GeneCDC14A	AuthorityHGNC:1718	Mapping file id8556 NCBI file	EvidenceTAS
GeneCDC14B	AuthorityHGNC:1719	Mapping file id8555 NCBI file	EvidenceTAS
GeneCDC42	AuthorityHGNC:1736	Mapping file id998 NCBI file	EvidenceTAS
GeneCDC42EP2	AuthorityHGNC:16263	Mapping file id10435 NCBI file	EvidenceTAS
GeneCDC42EP3	AuthorityHGNC:16943	Mapping file id10602 NCBI file	EvidenceTAS
GeneCDC42EP5	AuthorityHGNC:17408	Mapping file id148170 NCBI file	EvidenceTAS
GeneCDK1	AuthorityHGNC:1722	Mapping file id983 NCBI file	EvidenceTAS
GeneDNAJB1	AuthorityHGNC:5270	Mapping file id3337 NCBI file	EvidenceTAS
GeneETV4	AuthorityHGNC:3493	Mapping file id2118 NCBI file	EvidenceTAS
GeneFOXO1	AuthorityHGNC:3819	Mapping file id2308 NCBI file	EvidenceTAS
GeneFOXO3	AuthorityHGNC:3821	Mapping file id2309 NCBI file	EvidenceTAS
GeneHSPB1	AuthorityHGNC:5246	Mapping file id3315 NCBI file	EvidenceTAS
GeneIGF2BP1	AuthorityHGNC:28866	Mapping file id10642 NCBI file	EvidenceTAS
GeneJUN	AuthorityHGNC:6204	Mapping file id3725 NCBI file	EvidenceTAS
GeneKALRN	AuthorityHGNC:4814	Mapping file id8997 NCBI file	EvidenceTAS
GeneMAPK4	AuthorityHGNC:6878	Mapping file id5596 NCBI file	EvidenceTAS
GeneMAPK6	AuthorityHGNC:6879	Mapping file id5597 NCBI file	EvidenceTAS
GeneMAPKAPK5	AuthorityHGNC:6889	Mapping file id8550 NCBI file	EvidenceTAS
GeneMIR34B	AuthorityHGNC:31636	Mapping file idENSG00000207811 Ensembl file	EvidenceTAS
GeneMIR34C	AuthorityHGNC:31637	Mapping file idENSG00000207562 Ensembl file	EvidenceTAS
GeneMMP10	AuthorityHGNC:7156	Mapping file idENSG00000166670 Ensembl file	EvidenceTAS
GeneMMP2	AuthorityHGNC:7166	Mapping file idENSG00000087245 Ensembl file	EvidenceTAS
GeneMOV10	AuthorityHGNC:7200	Mapping file id4343 NCBI file	EvidenceTAS
GeneMYC	AuthorityHGNC:7553	Mapping file id4609 NCBI file	EvidenceTAS
GeneNCOA3	AuthorityHGNC:7670	Mapping file id8202 NCBI file	EvidenceTAS
GenePAK1	AuthorityHGNC:8590	Mapping file id5058 NCBI file	EvidenceTAS
GenePAK2	AuthorityHGNC:8591	Mapping file id5062 NCBI file	EvidenceTAS
GenePAK3	AuthorityHGNC:8592	Mapping file id5063 NCBI file	EvidenceTAS
GenePRKACA	AuthorityHGNC:9380	Mapping file id5566 NCBI file	EvidenceTAS
GenePRKACB	AuthorityHGNC:9381	Mapping file id5567 NCBI file	EvidenceTAS
GenePRKACG	AuthorityHGNC:9382	Mapping file id5568 NCBI file	EvidenceTAS
GenePSMA1	AuthorityHGNC:9530	Mapping file id5682 NCBI file	EvidenceTAS
GenePSMA2	AuthorityHGNC:9531	Mapping file id5683 NCBI file	EvidenceTAS
GenePSMA3	AuthorityHGNC:9532	Mapping file id5684 NCBI file	EvidenceTAS
GenePSMA4	AuthorityHGNC:9533	Mapping file id5685 NCBI file	EvidenceTAS
GenePSMA5	AuthorityHGNC:9534	Mapping file id5686 NCBI file	EvidenceTAS
GenePSMA6	AuthorityHGNC:9535	Mapping file id5687 NCBI file	EvidenceTAS
GenePSMA7	AuthorityHGNC:9536	Mapping file id5688 NCBI file	EvidenceTAS
GenePSMB1	AuthorityHGNC:9537	Mapping file id5689 NCBI file	EvidenceTAS
GenePSMB2	AuthorityHGNC:9539	Mapping file id5690 NCBI file	EvidenceTAS
GenePSMB3	AuthorityHGNC:9540	Mapping file id5691 NCBI file	EvidenceTAS
GenePSMB4	AuthorityHGNC:9541	Mapping file id5692 NCBI file	EvidenceTAS
GenePSMB5	AuthorityHGNC:9542	Mapping file id5693 NCBI file	EvidenceTAS
GenePSMB6	AuthorityHGNC:9543	Mapping file id5694 NCBI file	EvidenceTAS
GenePSMB7	AuthorityHGNC:9544	Mapping file id5695 NCBI file	EvidenceTAS
GenePSMC1	AuthorityHGNC:9547	Mapping file id5700 NCBI file	EvidenceTAS
GenePSMC2	AuthorityHGNC:9548	Mapping file id5701 NCBI file	EvidenceTAS
GenePSMC3	AuthorityHGNC:9549	Mapping file id5702 NCBI file	EvidenceTAS
GenePSMC4	AuthorityHGNC:9551	Mapping file id5704 NCBI file	EvidenceTAS
GenePSMC5	AuthorityHGNC:9552	Mapping file id5705 NCBI file	EvidenceTAS
GenePSMC6	AuthorityHGNC:9553	Mapping file id5706 NCBI file	EvidenceTAS
GenePSMD1	AuthorityHGNC:9554	Mapping file id5707 NCBI file	EvidenceTAS
GenePSMD11	AuthorityHGNC:9556	Mapping file id5717 NCBI file	EvidenceTAS
GenePSMD12	AuthorityHGNC:9557	Mapping file id5718 NCBI file	EvidenceTAS
GenePSMD13	AuthorityHGNC:9558	Mapping file id5719 NCBI file	EvidenceTAS
GenePSMD14	AuthorityHGNC:16889	Mapping file id10213 NCBI file	EvidenceTAS
GenePSMD2	AuthorityHGNC:9559	Mapping file id5708 NCBI file	EvidenceTAS
GenePSMD3	AuthorityHGNC:9560	Mapping file id5709 NCBI file	EvidenceTAS
GenePSMD6	AuthorityHGNC:9564	Mapping file id9861 NCBI file	EvidenceTAS
GenePSMD7	AuthorityHGNC:9565	Mapping file id5713 NCBI file	EvidenceTAS
GenePSMD8	AuthorityHGNC:9566	Mapping file id5714 NCBI file	EvidenceTAS
GeneRAC1	AuthorityHGNC:9801	Mapping file id5879 NCBI file	EvidenceTAS
GeneRAG1	AuthorityHGNC:9831	Mapping file id5896 NCBI file	EvidenceTAS
GeneRAG2	AuthorityHGNC:9832	Mapping file id5897 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSEM1	AuthorityHGNC:10845	Mapping file id7979 NCBI file	EvidenceTAS
GeneSEPTIN7	AuthorityHGNC:1717	Mapping file id989 NCBI file	EvidenceTAS
GeneTNRC6A	AuthorityHGNC:11969	Mapping file id27327 NCBI file	EvidenceTAS
GeneTNRC6B	AuthorityHGNC:29190	Mapping file id23112 NCBI file	EvidenceTAS
GeneTNRC6C	AuthorityHGNC:29318	Mapping file id57690 NCBI file	EvidenceTAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceTAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceTAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceTAS
GeneXPO1	AuthorityHGNC:12825	Mapping file id7514 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

MAPK family signaling cascadesR-HSA-5683057317 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.