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MAPK7 (mitogen-activated protein kinase 7)
Francisco de Asís Iñesta-Vaquera, Ana Cuenda
Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (FdAIV,
AC)
Published in Atlas Database: February 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK7ID41294ch17p11.html
DOI: 10.4267/2042/44909
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
(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).
Identity
Other names: BMK1, ERK4, ERK5, PRKM7
HGNC (Hugo): MAPK7
Location: 17p11.2
Pseudogene
DNA/RNA
Protein
Description
Note
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.
No human or mouse pseudogene known.
The MAPK7 entire gene spans 5,82 kb on the short arm
of chromosome 17. It contains 6 exons.
Transcription
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
MAPK7 genomic context (Chromosome 17; location 17p11.2).
Genomic organization of MAPK7 gene on chromosome 17p11.2.
The boxes indicate coding regions (exons 1-6) of the gene.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
1111
MAPK7 (mitogen-activated protein kinase 7)
Iñesta-Vaquera FdA, Cuenda A
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.
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.
Function
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 ERK5NFKappaB 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,
Description
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).
Expression
ERK5 (MAPK7) mRNA
throughout all tissues.
is
widely
expressed
Localisation
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 Cterminal halves is disrupted, and therefore ERK5 enters
the nucleus (Kondoh et al., 2006).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
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MAPK7 (mitogen-activated protein kinase 7)
Iñesta-Vaquera FdA, Cuenda A
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).
References
Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee
JD. Bmk1/Erk5 is required for cell proliferation induced by
epidermal growth factor. Nature. 1998 Oct 15;395(6703):713-6
Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y,
Lee JD. BMK1 mediates growth factor-induced cell proliferation
through direct cellular activation of serum and glucocorticoidinducible kinase. J Biol Chem. 2001 Mar 23;276(12):8631-4
Yan C, Luo H, Lee JD, Abe J, Berk BC. Molecular cloning of
mouse ERK5/BMK1 splice variants and characterization of
ERK5 functional domains. J Biol Chem. 2001 Apr
6;276(14):10870-8
Esparís-Ogando A, Díaz-Rodríguez E, Montero JC, Yuste L,
Crespo P, Pandiella A. Erk5 participates in neuregulin signal
transduction and is constitutively active in breast cancer cells
overexpressing ErbB2. Mol Cell Biol. 2002 Jan;22(1):270-85
Homology
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).
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S.
The protein kinase complement of the human genome.
Science. 2002 Dec 6;298(5600):1912-34
Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K. Erk5
null mice display multiple extraembryonic vascular and
embryonic cardiovascular defects. Proc Natl Acad Sci U S A.
2002 Jul 9;99(14):9248-53
Sohn SJ, Sarvis BK, Cado D, Winoto A. ERK5 MAPK regulates
embryonic angiogenesis and acts as a hypoxia-sensitive
repressor of vascular endothelial growth factor expression. J
Biol Chem. 2002 Nov 8;277(45):43344-51
Mutations
Note
Not identified.
Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C,
Lee JD, Abe J, Yang J. Regulation of epidermal growth factorinduced connexin 43 gap junction communication by big
mitogen-activated protein kinase1/ERK5 but not ERK1/2
kinase activation. J Biol Chem. 2003 May 16;278(20):18682-8
Implicated in
Breast cancer
Mody N, Campbell DG, Morrice N, Peggie M, Cohen P. An
analysis of the phosphorylation and activation of extracellularsignal-regulated protein kinase 5 (ERK5) by mitogen-activated
protein kinase kinase 5 (MKK5) in vitro. Biochem J. 2003 Jun
1;372(Pt 2):567-75
Note
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).
Mulloy R, Salinas S, Philips A, Hipskind RA. Activation of cyclin
D1 expression by the ERK5 cascade. Oncogene. 2003 Aug
21;22(35):5387-98
Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and
Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003
Mar;8(3):263-73
Prostatic cancer
Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur
JS. Knockout of ERK5 causes multiple defects in placental and
embryonic development. BMC Dev Biol. 2003 Dec 16;3:11
Note
ERK5 (MAPK7) immunoreactivity is significantly upregulated 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).
Cavanaugh JE. Role of extracellular signal regulated kinase 5
in neuronal survival. Eur J Biochem. 2004 Jun;271(11):2056-9
Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED,
Eliceiri B, Yang Y, Ulevitch RJ, Lee JD. Targeted deletion of
BMK1/ERK5 in adult mice perturbs vascular integrity and leads
to endothelial failure. J Clin Invest. 2004 Apr;113(8):1138-48
Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5
MAP kinase pathways can lead to disruption of the actin
cytoskeleton. J Cell Sci. 2005 Apr 15;118(Pt 8):1663-71
Hepatic carcinoma
Note
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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
Carvajal-Vergara X, Tabera S, Montero JC, Esparís-Ogando A,
López-Pérez R, Mateo G, Gutiérrez N, Parmo-Cabañas M,
Teixidó J, San Miguel JF, Pandiella A. Multifunctional role of
Erk5 in multiple myeloma. Blood. 2005 Jun 1;105(11):4492-9
Wang X, Merritt AJ, Seyfried J, Guo C, Papadakis ES, Finegan
KG, Kayahara M, Dixon J, Boot-Handford RP, Cartwright EJ,
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MAPK7 (mitogen-activated protein kinase 7)
Iñesta-Vaquera FdA, Cuenda A
Mayer U, Tournier C. Targeted deletion of mek5 causes early
embryonic death and defects in the extracellular signalregulated kinase 5/myocyte enhancer factor 2 cell survival
pathway. Mol Cell Biol. 2005 Jan;25(1):336-45
Sohn SJ, Lewis GM, Winoto A. Non-redundant function of
Watanabe N, Nagamatsu Y, Gengyo-Ando K, Mitani S,
Ohshima Y. Control of body size by SMA-5, a homolog of MAP
kinase BMK1/ERK5, in C. elegans. Development. 2005
Jul;132(14):3175-84
Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C.
Regulation of neuronal survival by the extracellular signalregulated protein kinase 5. Cell Death Differ. 2009
May;16(5):674-83
Kondoh K, Terasawa K, Morimoto H, Nishida E. Regulation of
nuclear translocation of extracellular signal-regulated kinase 5
by active nuclear import and export mechanisms. Mol Cell Biol.
2006 Mar;26(5):1679-90
Montero JC, Ocaña A, Abad M, Ortiz-Ruiz MJ, Pandiella A,
Esparís-Ogando A. Expression of Erk5 in early stage breast
cancer and association with disease free survival identifies this
kinase as a potential therapeutic target. PLoS One.
2009;4(5):e5565
the MEK5-ERK5 pathway in thymocyte apoptosis. EMBO J.
2008 Jul 9;27(13):1896-906
Truman AW, Millson SH, Nuttall JM, King V, Mollapour M,
Prodromou C, Pearl LH, Piper PW. Expressed 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. Eukaryot Cell.
2006 Nov;5(11):1914-24
Sawhney RS, Liu W, Brattain MG. A novel role of ERK5 in
integrin-mediated cell adhesion and motility in cancer cells via
Fak signaling. J Cell Physiol. 2009 Apr;219(1):152-61
Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler
M, Wegener J, Wixler V, Ludwig S. MEK5/ERK5 signaling
modulates endothelial cell migration and focal contact turnover.
J Biol Chem. 2009 Sep 11;284(37):24972-80
Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang H, Wang CY, Xia
Z. Regulation of the G2-M cell cycle progression by the ERK5NFkappaB signaling pathway. J Cell Biol. 2007 Apr
23;177(2):253-64
Zen K, Yasui K, Nakajima T, Zen Y, Zen K, Gen Y, Mitsuyoshi
H, Minami M, Mitsufuji S, Tanaka S, Itoh Y, Nakanuma Y,
Taniwaki M, Arii S, Okanoue T, Yoshikawa T. ERK5 is a target
for gene amplification at 17p11 and promotes cell growth in
hepatocellular carcinoma by regulating mitotic entry. Genes
Chromosomes Cancer. 2009 Feb;48(2):109-20
Morimoto H, Kondoh K, Nishimoto S, Terasawa K, Nishida E.
Activation of a C-terminal transcriptional activation domain of
ERK5 by autophosphorylation. J Biol Chem. 2007 Dec
7;282(49):35449-56
McCracken SR, Ramsay A, Heer R, Mathers ME, Jenkins BL,
Edwards J, Robson CN, Marquez R, Cohen P, Leung HY.
Aberrant expression of extracellular signal-regulated kinase 5
in human prostate cancer. Oncogene. 2008 May
8;27(21):2978-88
This article should be referenced as such:
Iñesta-Vaquera FdA, Cuenda A. MAPK7 (mitogen-activated
protein kinase 7). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(12):1111-1114.
Schramp M, Ying O, Kim TY, Martin GS. ERK5 promotes Srcinduced podosome formation by limiting Rho activation. J Cell
Biol. 2008 Jun 30;181(7):1195-210
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
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