MAPK7 (mitogen-activated protein kinase 7)

2010-02-01   Francisco de Asís Iñesta-Vaquera , Ana Cuenda 

Centro Nacional de Biotecnologia-CSIC, Department of Immunology, Oncology, Madrid, Spain


Atlas Image
MAPK7 genomic context (Chromosome 17; location 17p11.2).


Atlas Image
Genomic organization of MAPK7 gene on chromosome 17p11.2. The boxes indicate coding regions (exons 1-6) of the gene.


The MAPK7 entire gene spans 5,82 kb on the short arm of chromosome 17. It contains 6 exons.


The human MAPK7 gene encodes an 816 amino-acids protein of about 98 kDa. MAPK7 mRNA is 2445 bp. There are 11 transcripts, seven of which are protein coding. In mice, three splice variants (MAPK7a, b and c) have been reported. Mouse splice variants are generated by alternative splicing across introns 1 and/or 2 (Yan et al., 2001).


No human or mouse pseudogene known.



ERK5, also known as MAPK7 or "Big MAP-Kinase 1" (BMK1) belongs to the Mitogen Activated Protein Kinase (MAPK) family, and therefore to the CGMC kinases in the human kinome (Manning et al., 2002). ERK5, at 98 kDa, is twice the size of other MAPKs and hence the largest kinase within its group. It possesses a catalytic N-terminal domain, which share 50% homology with ERK1 (MAPK3) and ERK2 (MAPK1) and a unique C-terminal tail of about 400 amino-acids long. In vivo, ERK5 is activated to the same extent by environmental stresses, such as oxidative and osmotic shock, and by growth factors. In addition, ERK5 may be activated by the cytokine Interleukin-6 in B cells.
Atlas Image
Schematic representation of the human ERK5 (MAPK7) protein domains. NES1 and NES2, bipartite nuclear exportation signal; PB1-BD, PB1 (Phox and Bem domain 1) binding domain; Kinase Domain, catalytic kinase domain; TEY, sequence motif containing ERK5 regulatory phosphorylation residues; PR-1 and PR-2, proline rich domains; Transcriptional trans-activation, transcriptional activity domain.


Human ERK5 (MAPK7) is a Ser/Thr protein kinase of 816 amino-acids with a predicted mass of 98 kDa. The ERK5 N-terminus domain resembles the typical MAPK catalytic domain and includes the MAPK-conserved TXY activation sequence (T218EY220) in the activation loop. The activation of ERK5 occurs via interaction with and dual phosphorylation in its TEY motif by MKK5 (Mody et al., 2003). MKK5 mediated ERK5 activation leads to ERK5 autophosphorylation in its unique C-terminal domain (Morimoto et al., 2007).


ERK5 (MAPK7) mRNA is widely expressed throughout all tissues.


Both in tissues and in cultured cells, ERK5 (MAPK7) localizes to the cytoplasm of cells and/or to the nucleus. As shown in the above diagram, ERK5 molecule contains a bipartite nuclear exportation signal. In resting cells, the N- and C-terminal halves of ERK5 interact producing a nuclear export signal (NES) that retains ERK5 in the cytoplasm of the cells. Upon stimulation, the interaction between the N- and the C-terminal halves is disrupted, and therefore ERK5 enters the nucleus (Kondoh et al., 2006).


Genetic studies have shown that ERK5 (MAPK7) is essential for cardiovascular development and neuronal differentiation. ERK5 knock-out mice die at midgestation due to developmental failures in structures as placenta, heart and vascular system (Regan et al., 2002; Sohn et al., 2002; Yan et al., 2003; Hayashi et al., 2004; Wang et al., 2005). ERK5 also regulates cell survival in a variety of tissues. At nervous system, ERK5 acts as a neuroprotector from neurotrophic factor withdrawal and toxic insults (Cavanaugh, 2004). Also, ERK5 is required to mediate the survival response of neurons to nerve growth factor (Finegan et al., 2009). In the immune system, the ERK5 pathway regulates apoptosis of developing thymocytes (Sohn et al., 2008) and protects B cells from proapoptotic stimuli (Carvajal-Vergara et al., 2005). ERK5 is also required for cell cycle progression. It regulates cyclin D1 expression (Mulloy et al., 2003) and is necessary for EGF-induced cell proliferation and progression through the cell cycle (Kato et al., 1998). Moreover, it has been suggested that the ERK5-NFKappaB pathway may be required for a timely mitotic entry (Cude et al., 2007). Additionally, ERK5, along with other MAPK pathways can play an indirect role in cytoskeleton rearrangement (Barros and Marshall, 2005), in promoting SRC-induced podosome formation (Schramp et al., 2008), and in cell attachment to the extracellular matrix and in endothelial cell migration (Spiering et al., 2009; Sawhney et al., 2009).
ERK5 (MAPK7) is a protein with kinase activity (in its N-terminal region) and also transcriptional activation activity (in the C-terminal half). Downstream targets of ERK5 include the transcription factors MEF2A, MEF2C and MEF2D, SAP1a, c-Myc and CREB. For example, ERK5 phosphorylates SAP1, which enhances its transcriptional activity promoting c-FOS expression (Terasawa et al., 2003), and activates the serum- and glucocorticoid-inducible kinase1 (SGK1) by phosphorylating Ser78 in response to growth factors (Hayashi et al., 2001). In cardiac tissue, ERK5 may couple cells electrically and metabolically by phosphorylating the gap-junction protein Cx43 at a key residue for gap junction communication (Cameron et al., 2003). Also, phosphorylated ERK5 regulates gene expression through its C-terminal transcriptional activation domain (Morimoto et al., 2007).


ERK5 (MAPK7) N-terminal half shares a 50% sequence identity with ERK1/2. The homology of the C-terminal part of ERK5 with other protein has not been reported. ERK5 possesses ortholog in the majority of mammals (sharing 80-98% homology). In C. elegans, the SMA-5 protein is a 60% similar to human ERK5 (Watanabe et al., 2005). In Saccharomyces cerevisiae, Slt2p (Mpk1p) is an ERK5 ortholog (Truman et al., 2006).



Not identified.

Implicated in

Entity name
Breast cancer
ERK5 (MAPK7) expression and activity is increased in breast cancer tumours. ERK5 overexpression has been established as an independent predictor of disease-free survival in breast cancer (Montero et al., 2009). In cell models, ERK5 has been linked to the regulation of breast cancer cells proliferation (Esparís-Ogando et al., 2002).
Entity name
Prostatic cancer
ERK5 (MAPK7) immunoreactivity is significantly up-regulated in high-grade prostate cancer. Increased ERK5 cytoplasmic signals correlated with metastases and locally advanced disease at diagnosis. Strong nuclear ERK5 localization in prostatic tumours correlates with poor disease-specific survival (McCracken et al., 2008).
Entity name
Hepatic carcinoma
An increase in ERK5 (MAPK7) copy number was detected in primary HCC tumours. It has been suggested that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein promotes the growth of hepatic carcinoma cells by regulating mitotic entry (Zen et al., 2009).


Pubmed IDLast YearTitleAuthors
157979232005Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton.Barros JC et al
126375022003Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation.Cameron SJ et al
156920642005Multifunctional role of Erk5 in multiple myeloma.Carvajal-Vergara X et al
151530942004Role of extracellular signal regulated kinase 5 in neuronal survival.Cavanaugh JE et al
174525292007Regulation of the G2-M cell cycle progression by the ERK5-NFkappaB signaling pathway.Cude K et al
117397402002Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2.Esparís-Ogando A et al
191481852009Regulation of neuronal survival by the extracellular signal-regulated protein kinase 5.Finegan KG et al
150851932004Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure.Hayashi M et al
112546542001BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase.Hayashi M et al
97901941998Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor.Kato Y et al
164789892006Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms.Kondoh K et al
124712432002The protein kinase complement of the human genome.Manning G et al
180713192008Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer.McCracken SR et al
126280022003An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro.Mody N et al
194405382009Expression of Erk5 in early stage breast cancer and association with disease free survival identifies this kinase as a potential therapeutic target.Montero JC et al
179282972007Activation of a C-terminal transcriptional activation domain of ERK5 by autophosphorylation.Morimoto H et al
129340982003Activation of cyclin D1 expression by the ERK5 cascade.Mulloy R et al
120939142002Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects.Regan CP et al
190899932009A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling.Sawhney RS et al
185739162008ERK5 promotes Src-induced podosome formation by limiting Rho activation.Schramp M et al
185480092008Non-redundant function of the MEK5-ERK5 pathway in thymocyte apoptosis.Sohn SJ et al
122210992002ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression.Sohn SJ et al
196053612009MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover.Spiering D et al
126227232003Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway.Terasawa K et al
169509282006Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase.Truman AW et al
156018542005Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway.Wang X et al
159441832005Control of body size by SMA-5, a homolog of MAP kinase BMK1/ERK5, in C. elegans.Watanabe N et al
111395782001Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains.Yan C et al
146754802003Knockout of ERK5 causes multiple defects in placental and embryonic development.Yan L et al
189731382009ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry.Zen K et al

Other Information

Locus ID:

NCBI: 5598
MIM: 602521
HGNC: 6880
Ensembl: ENSG00000166484


dbSNP: 5598
ClinVar: 5598
TCGA: ENSG00000166484


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Gap junctionKEGGko04540
GnRH signaling pathwayKEGGko04912
MAPK signaling pathwayKEGGhsa04010
Gap junctionKEGGhsa04540
GnRH signaling pathwayKEGGhsa04912
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
MAPK (ERK5) signalingKEGGhsa_M00690
MAPK (ERK5) signalingKEGGM00690
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
ERKs are inactivatedREACTOMER-HSA-202670
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERK5REACTOMER-HSA-198765
Nuclear Events (kinase and transcription factor activation)REACTOMER-HSA-198725
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
RET signalingREACTOMER-HSA-8853659
IL-17 signaling pathwayKEGGko04657
Fluid shear stress and atherosclerosisKEGGko05418
IL-17 signaling pathwayKEGGhsa04657
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
208327532010Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein.80
198558442009miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.75
205513242010Erk5 activation elicits a vasoprotective endothelial phenotype via induction of Kruppel-like factor 4 (KLF4).56
168352282006Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma.52
126375022003Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation.42
187160622008Erk5 controls Slug expression and keratinocyte activation during wound healing.42
263474732015A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.41
170182932006Spatiotemporal regulation of c-Fos by ERK5 and the E3 ubiquitin ligase UBR1, and its biological role.39
174525292007Regulation of the G2-M cell cycle progression by the ERK5-NFkappaB signaling pathway.39


Francisco de Asís Iñesta-Vaquera ; Ana Cuenda

MAPK7 (mitogen-activated protein kinase 7)

Atlas Genet Cytogenet Oncol Haematol. 2010-02-01

Online version: