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Signalling 2011: a Biochemical Society Centenary Celebration
ERK5 and its role in tumour development
Pamela A. Lochhead1 , Rebecca Gilley and Simon J. Cook
Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
Abstract
The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase
5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in
the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the
‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing
a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5
is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate
ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by
down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for
further investigation into understanding the role of ERK5 in cancer.
Introduction
ERK (extracellular-signal-regulated kinase) 5 is the effector kinase of a canonical three-tiered MAPK (mitogenactivated protein kinase) signalling cascade comprising MEK
(MAPK/ERK kinase) 5, MEKK (MEK kinase) 2/3 and ERK5
itself [1,2]. The ERK5 protein, encoded by the MAPK7
gene [1], contains an N-terminal kinase domain that shares
50% identity with ERK2, and a large C-terminal extension
that contains a transactivation domain, an NLS (nuclear
localization sequence), an NES (nuclear export sequence) and
two proline-rich regions [1,3,4] (Figure 1). Owing to its large
size, ERK5 is sometimes referred to as BMK1 (big MAPK1)
[2].
In normal physiology, MEK5 and ERK5 are ubiquitously
expressed [1,2,5] and are activated by growth factors and
cellular stresses [6–8]. In development, the MEK5/ERK5
pathway is important for blood vessel and cardiac development, as removal of Mek5 or Erk5 is embryonic lethal at E
(embryonic day) 9.5–10.5 with defects in these tissues [9,10].
Using an in vitro muscle differentiation system, ERK5 has
also been shown to be important for muscle development [11],
whereas, in the adult, the MEK5/ERK5 pathway is important
in regulating the proliferation and survival of endothelial cells
[12–14] and cells of the immune system [15,16].
In cancer, there is clinical evidence that an increase
in MEK5/ERK5 signalling may be important for disease
progression. For example, in breast cancer, MEK5 expression
is up-regulated by constitutive activation of STAT (signal
Key words: angiogenesis, cancer, extracellular-signal-regulated kinase 5 (ERK5), microRNA
(miRNA), migration, oncogene.
Abbreviations used: CDK1, cyclin-dependent kinase 1; ECM, extracellular matrix; EGF, epidermal
growth factor; EGFR, EGF receptor; ERK, extracellular-signal-regulated kinase; HCC, hepatocellular
carcinoma; IL-6, interleukin 6; MAPK, mitogen-activated protein kinasel; MEF, mouse embryonic
fibroblast; MEK, MAPK/ERK kinase; miRNA, microRNA; MMP, matrix metalloprotease; NF-κB,
nuclear factor κB; NRG, neuregulin; PKB, protein kinase B; RNAi, RNA interference; STAT, signal
transducer and activator of transcription; TNFα, tumour necrosis factor α, TRAIL, TNFα (tumour
necrosis factor α)-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.
1
To whom correspondence should be addressed (email pamela.lochhead@babraham.
ac.uk).
Biochem. Soc. Trans. (2012) 40, 251–256; doi:10.1042/BST20110663
transducer and activator of transcription) 3 [17]. Constitutive
activation of STAT3 is frequently detected in patients with
advanced breast cancer, but not in normal breast epithelial
cells [18]. Furthermore, increased ERK5 protein levels
are associated with decreased disease-free survival [19]. In
prostate cancer, MEK5 is overexpressed and correlates with
the presence of bone metastases and less favourable diseasespecific survival [20]. Furthermore, ERK5 is a target for gene
amplification at 17p11 in HCC (hepatocellular carcinoma),
an amplification detected in approximately 50% of primary
HCC tumours [21].
ERK5 activity has also been shown to be activated by some
oncogenes, and its protein levels are subject to regulation by
tumour-suppressive miRNAs (microRNAs), suggesting that
targeted therapies against ERK5 may have a more widespread
clinical application than the cancers described above. In the
present review, we assess the rationale for targeting ERK5 using the ‘hallmarks of cancer’ [22] as a framework, discuss the
evidence for ERK5 activation by oncogenes and consider
the mechanisms that regulate ERK5 protein levels.
ERK5 and the hallmarks of cancer
The hallmarks of cancer are an organizing framework of
biological capabilities that allows the complexity of tumour
development to be rationalized. The eight hallmarks are
sustaining proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality,
inducing angiogenesis, activating invasion and metastasis,
reprogramming of energy metabolism, and evading immune
destruction. These hallmarks are acquired by normal
cells during tumour pathogenesis to produce tumorigenic
and malignant cells [22]. However, it is important to
note that tumours are not simply an isolated mass of
proliferating cancer cells; the tumour microenvironment aids
tumorigenesis as there are essential interactions between
the surrounding stromal cells and the tumour cells [22].
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Figure 1 Schematic representation of the role and regulation of
ERK5 by growth factors, oncogenes and during mitosis
KD, kinase domain; TAD, transactivation domain; 䊊, phosphorylation sites
[3,39–40,42]. Data from PhosphoSitePlus (http://www.phosphosite.
org) and PHOSIDA, the Posttranslational Modification Database
(http://www.phosida.de).
Nevertheless, the hallmarks of cancer provide a critical
framework for assessing the role of genes in promoting or
sustaining the cancer cell phenotype.
Sustaining proliferative signalling
Cancer cells sustain proliferation by autocrine proliferative
signals, overexpression of cell-surface receptors and/or
constitutive activation of signalling pathway components.
They typically become ‘addicted’ to key pathways for
their proliferation (and survival), therefore defining the
components of these pathways is important. ERK5 was first
demonstrated to be important for cancer cell proliferation
in HeLa cells [23], where a dominant-negative form of
ERK5 (the residues phosphorylated by MEK5 are mutated
to alanine or phenylalanine: an AEF motif rather than a
TEY motif) blocked entry into S-phase in response to EGF
(epidermal growth factor). Similar studies have suggested a
role for ERK5 in the proliferation of the MCF7 and BT474
breast cancer cell lines [24], the immortalized breast epithelial
cell line MCF10A [23] and in multiple myeloma MM1S cells
[7]. Furthermore, expression of a constitutively active form of
MEK5 (the activation-loop residues are mutated to aspartic
acid to mimic phosphorylation; MEK5D) increased the
proliferation of HEK (human embryonic kidney)-293 cells
and the prostate cancer cell line LNCaP [20]. RNAi (RNA
interference) techniques have confirmed the requirement for
ERK5 in cell proliferation of LNCaP and C4-2 cells [25]
and in T24 bladder cells [26]. It should be noted that,
although ectopic expression of ERK5 in the prostate cancer
cell line PC3 increased proliferation, RNAi knockdown did
not decrease proliferation [27]. This suggests that the role of
ERK5 in sustaining the proliferative signal may be
cancer-cell-line- or tumour-specific, and at this time, it
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Authors Journal compilation is unknown what makes a cancer cell sensitive to ERK5
inhibition.
Resisting cell death
Although cancer cells are under continual stress caused
by oncogenic signalling and DNA damage associated
with hyperproliferation, they have devised mechanisms to
evade apoptosis. The most common mechanism is loss
or inactivation of the tumour suppressor p53. Other
mechanisms include up-regulation of pro-survival proteins
(i.e. Bcl-2) or down-regulation of pro-apoptotic proteins (i.e.
Bax and Bim). These proteins are under direct regulation
by signalling cascades. The MEK5/ERK5 cascade has been
shown to protect cells from apoptotic stimuli as Mek5 − / −
MEFs (mouse embryonic fibroblasts) are more sensitive to
osmotic-stress-induced apoptosis [10] and overexpression
of a nuclear-localized ERK5 mutant (570) protects HeLa
cells from TRAIL [TNFα (tumour necrosis factor α)-related
apoptosis-inducing ligand]-induced apoptosis [28]. Indeed,
MEK5 and ERK5 are required for resistance of MCF7
cells to apoptosis induced by etoposide, TRAIL and TNFα
[29]. Overexpression of ERK5 protects multiple myeloma
cells from PS431-induced apoptosis, whereas overexpression
of the non-activatable mutant (AEF) sensitizes them to
apoptosis induced by PS431 and dexamethasone [7]. ERK5
knockdown by shRNA (small hairpin RNA) sensitizes Tlymphocytes to Fas-induced apoptosis. This pro-survival
role of ERK5 was mediated by NF-κB (nuclear factor
κB) activation and nuclear localization [30]. NF-κB nuclear
localization has been observed in many cancers [31] and
is thought to play an important role in promoting cell
survival. Despite these examples, there is relatively little
direct evidence that cancer cells have evolved to be dependent
upon endogenous ERK5 signalling for survival, certainly in
comparison with recognized cell survival kinases such as PKB
(protein kinase B) and ERK1/2.
Activating invasion and metastasis
Cancers of epithelial origin progress to invade local tissues
and metastasize to distal sites. This requires changes
in cell shape, decreased attachment to other cells and
the ECM (extracellular matrix) and an increase in cell
motility. In advanced prostate cancer, high MEK5 levels are
associated with bone metastasis [20] and in advanced OSCC
(oral squamous cell carcinoma), high ERK5 expression is
associated with the presence of lymph node metastases
[32]. In keeping with these observations, overexpression of
ERK5 in an orthotopic model of prostate cancer induced
metastasis to the lymph nodes and lungs [27]. In experimental
systems, ERK5 has been demonstrated to have a role in
the formation of invadopodia in A375 malignant melanoma
and PC3 prostate cancer cells [27] and podosomes in MEFs
[33]. Invadopodia and podosomes are dynamic, actin-based
protrusions of the plasma membrane that are involved in cell
attachment to the ECM. They also contain MMPs (matrix
metalloproteases) that degrade the ECM and facilitate cell
motility/invasion [34]. Consistent with this function, ERK5
Signalling 2011: a Biochemical Society Centenary Celebration
regulates the expression of MMP2 and MMP9 [20,27] and the
degradation of synthetic ECM in vitro [27,33]. ERK5 also
plays a role in regulating actin dynamics and cell motility.
For example, ERK5 expression leads to the loss of stress
fibres in NIH 3T3 cells, and inhibition of both ERK5
and ERK1/2 was required to restore stress fibres in Srctransformed NIH 3T3 cells [35]. Furthermore, reduction of
ERK5 levels by siRNA (small interfering RNA) reduced
both random cell migration and invasion into Matrigel in
PC3 cells [27] and HGF (hepatocyte growth factor)-induced
cell migration of MDA-MB-231 breast cancer cells [36].
This latter observation has been demonstrated to involve the
RNA processing protein, SAM-68 (Src-associated in mitosis
68 kDa) [37]. Taken together, these observations show that,
in cancer cells with aberrant ERK5 activity, ERK5 may play
a key role in co-ordinating migration and invasion.
Inducing angiogenesis
Tumours require a blood supply to deliver nutrients and
oxygen and to remove metabolic waste and carbon dioxide.
Angiogenesis is the sprouting of new blood vessels from
existing ones and, in tumour progression, there is an
‘angiogenic switch’ that causes quiescent vasculature to
continually sprout new blood vessels to sustain the growing
tumour. VEGF (vascular endothelial growth factor) is a
well-known inducer of angiogenesis. Genetic deletion of
Mek5 and Erk5 has demonstrated their important role in
blood vessel formation [9–11]. In addition, the role of ERK5
signalling in tumour-associated neovascularization has also
been tested directly. Targeted deletion of ERK5 in endothelial
cells reduced the mass and vascular density of tumours in
two xenograft models (B16F10 melanoma and LL/2 Lewis
lung). Similar results were seen in Matrigel plug assays
measuring neovascularization in response to VEGF and
bFGF (basic fibroblast growth factor). It is thought the
role that ERK5 plays in neovascularization is by mediating
endothelial cell proliferation and survival [38]. However, in
an in vitro angiogenesis system, ERK5 is required for VEGFinduced tubular morphogenesis, but not cell proliferation.
During tubular morphogenesis, ERK5 is required for VEGFstimulated PKB phosphorylation on Ser473 and Thr308 , Bad
phosphorylation on Ser136 and inhibition of caspase 3/7
activity [14]. These findings demonstrate the ERK5 is a
pivotal enzyme in regulating tumour angiogenesis.
Regulation and deregulation of ERK5
Model of ERK5 activation and regulation
In order to understand whether ERK5 is deregulated in
cancer, we must first consider how ERK5 is regulated under
‘normal’ conditions and how it mediates its functions. The
canonical activation mechanism of ERK5 involves MEK5
phosphorylation of the TEY motif in the activation loop of
the ERK5 kinase domain followed by autophosphorylation
of the C-terminal extension on multiple sites [5,39]
(Figure 1). The C-terminal extension inhibits the ERK5
kinase domain, whereas C-terminal autophosphorylation
relieves this autoinhibition [5]. The C-terminal extension
of ERK5 is also phosphorylated by a MEK5-independent
mechanism during mitosis, which requires the activity
of CDK1 (cyclin-dependent kinase 1) (although ERK5
may not be a direct CDK1 substrate) [40–42] (Figure 1).
Once active, and phosphorylated, ERK5 can function as a
kinase to phosphorylate substrates, but can also function
as a transcriptional transactivating factor [3,43] and play
a role in transcriptional elongation [44]. ERK5 is present
in both the nucleus and the cytosol and probably exists in
both inactive and active states in both compartments.
However, MEK5 phosphorylation of the ERK5 activation
loop and C-terminal autophosphorylation leads to an increase
in the nuclear localization of ERK5. There is one nonsynonymous somatic mutation in ERK5 reported in the
Catalogue of Somatic Mutations in Cancer (COSMIC)
(http://www.sanger.ac.uk/genetics/CGP/cosmic/). But with
over 900 samples sequenced, this makes mutation of ERK5
a very infrequent event in cancer. Deregulation of the
MEK5/ERK5 pathway is more likely to be achieved by
sustained activation and increased protein levels.
Regulation of ERK5 by growth factors and
oncogenes
Epidermal growth factor
EGF plays important role in the regulation of cell
proliferation, survival and differentiation. EGF binds to the
EGFR (EGF receptor), activates its intracellular tyrosine
kinase, which in turn activates intracellular signalling
cascades. EGF has been shown to activate ERK5 in many
cell types [14,23,24,45–47]. NRG (neuregulin), proteins
structurally related to EGF that activate erbB receptor
tyrosine kinases (erbB2–erbB4) and activate ERK5 in MCF7
breast cancer cells [24]. Activation of ERK5 in these systems
is primarily involved in promoting cell proliferation, so it
will be interesting to determine whether ERK5 is required in
cancers that contain overexpressed or mutated EGFR.
Src
Src, a proto-oncogenic non-receptor tyrosine kinase, is
required for activation of the ERK5 pathway in response
to some growth factors and cytokines. For example, Src is
required for ERK5 activation by PDGF (platelet-derived
growth factor) in hepatic stellate cells [45] and PAE
(porcine aortic endothelial) cells [48], but not by the
cytokine IL-6 (interleukin 6) in multiple myeloma cells
[7]. Src is also required for ERK5 activation by cellular
stresses such as hydrogen peroxide in fibroblasts [49] and
asbestos in lung epithelial cells [46], but not by fluid
shear stress in endothelial cells [50]. Oncogenic forms of
Src (v-Src and SrcY527F ) can activate the ERK5 pathway
in fibroblasts [33,35,49], leading to an increase in ERK5
nuclear localization [35]. Furthermore, ERK5 is required
for Src-driven transformation in NIH 3T3 fibroblasts, as
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dominant-negative forms of MEK5 (where the residues
required to be phosphorylated for activity are mutated to
alanine; AA) and ERK5 (AEF) block foci formation [35].
This raises the possibility that ERK5 is required to promote
transformation in cancers where Src is deregulated.
Copy Number Analysis (CONAN) website (http://www.
sanger.ac.uk/cgi-bin/genetics/CGP/conan/search.cgi). It will
be interesting to determine whether these cell lines have also
developed ERK5 ‘addiction’, similar to SNU449.
Regulation by miR-143
Ras and Raf
Ras
is
a
small
GTPase
that
activates
the
Raf/MEK1/2/ERK1/2 pathway. There are three human
Ras proteins, K-Ras, H-Ras and N-Ras, one or other of
which is mutated in approximately 20% of all tumours.
The Raf serine/threonine kinases (B-Raf, C-Raf and A-Raf)
are activated directly by GTP-bound Ras proteins, and
in turn activate the MEK1/2/ERK1/2 pathway. B-Raf
is also mutated and thereby activated at high frequency
in certain tumours. Studies indicate that the role of Ras in
ERK5 activation is highly cell-type-specific; for example, a
dominant-negative form of H-Ras (N17) inhibited ERK5
activation by EGF in rat phaeochromocytoma PC12 cells
and mouse myoblast C2C12 cells, but not in COS7 cells [8].
NRG-driven activation of ERK5 was independent of Ras in
breast cancer cells [24] and IL-6 activation of ERK5 was also
Ras-independent in multiple myeloma [7]. Interestingly, an
active form of H-Ras (12V) can activate the kinase domain
of ERK5 in co-expression studies [23,51], although the
physiological relevance of this is unclear. Similarly, MEK5D
co-operates with C-Raf (Raf-1) to transform NIH 3T3
cells [52], raising the possibility that in cancers that harbour
Ras and Raf mutations, ERK5 may be required for cell
transformation. However, this hypothesis has not yet been
thoroughly tested.
Tpl2 (tumour progression locus 2)/COT
COT is a serine/threonine protein kinase that has been
implicated in cellular transformation. It is a member of
the MAPK kinase kinase family and is overexpressed in
human gastric/colon adenocarcinomas, large granular T-cell
neoplasias, breast cancer and EBV (Epstein–Barr virus)related nasopharyngeal carcinoma and Hodgkin’s disease
[53]. COT causes cell transformation of NIH 3T3 fibroblasts
by increasing c-Jun expression, and this is mediated by cooperative signals from ERK5, p38γ and JNK (c-Jun Nterminal kinase) [54].
Increased expression of ERK5 in cancer
Amplification of ERK5
Although activating mutations in ERK5 are unknown, a novel
amplification has been identified at 17p11 in HCC (hepatocellular carcinoma). This contains the MAPK7 ERK5-encoding
gene and ERK5 protein is highly overexpressed in HCC cells
that exhibit this amplicon. This increase in MAPK7 copy
number was detected in 35/66 primary HCC tumours. The
SNU449 HCC cell line with the 17p11 amplification requires
ERK5 for proliferation [21]. There are four reports of other
cell lines with amplifications on the Cancer Genome Project’s
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Authors Journal compilation An exciting new level of regulation of ERK5 protein levels has
recently been discovered, namely regulation by the tumoursuppressive miRNAs miR-143 and miR-145 [25,26,55,56].
miRNAs regulate mRNA function by modulating mRNA
stability and translation. They are small non-coding singlestranded RNAs of approximately 22 nt in length and
primarily function by binding to the 3 -UTR (untranslated
region) of target mRNAs [57]. miR-143 and miR-145 are both
encoded by the same gene [58] and have both been shown
to down-regulate ERK5 protein levels [25,26,55,56]. Interestingly, miR-143 expression is decreased in prostate cancer
[25,27] and B-cell malignancies [55] and the bladder
cancer cell line T24 [26], where ERK5 expression is increased.
Reintroduction of synthetic miR-143 and miR-145 reduces
ERK5 levels and decreases cell proliferation of T24 bladder
cancer cells [26], LNCaP and C4-2 prostate cancer cells [25]
and Burkitt’s lymphoma Raji cells [55]. Similar results were
seen with RNAi knockdown of ERK5 in LNCaP and C4-2
[25] and T24 cells [26], suggesting that ERK5 is responsible
for these effects. Although miR-143 and miR-145 will have
multiple targets within the cell, it is possible that, in cancers
with down-regulated miR-143 and miR-145, ERK5 may play
a role in the aetiology of the disease.
Small-molecule inhibitors of MEK5 and
ERK5
There are currently three small-molecule inhibitors of
the MEK5/ERK5 pathway. The first to be described
were BIX02188 and BIX02189 by Boehringer Ingelheim
Pharmaceuticals [59]. These are selective inhibitors of MEK5
and do not inhibit MEK1/2. These have been used to
demonstrate a role for the MEK5/ERK5 pathway in nervegrowth-factor-induced neurite outgrowth and stabilization
of tyrosine hydroxylase in PC12 cells [60]. However,
to date, there are no data describing the effects of
these inhibitors on cancer cell proliferation, survival or
migration. The third newly described inhibitor is XMD892, a selective inhibitor of ERK5. Excitingly, XMD8-92 has
anti-proliferative effects on HeLa cells and inhibited the
growth of human tumour xenografts [HeLa (Nod/Scid)]
and syngenic mouse xenografts [LL/2 (B6)], suggesting that
ERK5 inhibitors may be potential cancer new therapies [61].
Summary
It is clear that the MEK5/ERK5 pathway plays an important
role in tumour neovascularization, and there is an emerging role in tumour cell invasion and metastasis. Furthermore,
there are multiple ways in which this pathway may
be deregulated in cancer. This suggests that MEK5- or
Signalling 2011: a Biochemical Society Centenary Celebration
ERK5-targeted therapies may have a more widespread clinical
application than first anticipated. With the advent of selective
small-molecule inhibitors of MEK5 and ERK5, and novel
miRNA therapeutic technologies, our understanding of the
role and requirement of MEK5 and ERK5 in cancer will
continue to grow.
Acknowledgements
We apologize to those authors whose work we have not been able
to cite due to limited space in the present review.
Funding
Our work is supported by the Babraham Institute, the Biotechnology
and Biological Sciences Research Council and grants from the
Association for International Cancer Research and Cancer Research
UK. P.A.L. is supported by a grant from the Association for
International Cancer Research awarded to S.J.C.
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Received 25 July 2011
doi:10.1042/BST20110663