Báo cáo khoa học: ERK and cell death: ERK1⁄2 in neuronal death Srinivasa Subramaniam1 and Klaus Unsicker2 pptx

MINIREVIEW
ERK and cell death: ERK1
⁄
2 in neuronal death
Srinivasa Subramaniam
1
and Klaus Unsicker
2
1 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, Germany
Neuronal death in the nervous system
Neuronal death is a major phenomenon in nervous
system development and a hallmark of all neurodegen-
erative diseases. Although numerous proteins have
been implicated in neuronal death, the detailed mecha-
nisms of how neurons succumb to death is far from
clear. Signals for cell death can emanate from the cell
surface or within the cell cytoplasm, mitochondria or
nucleus [1–3]. Caspases are a well-characterized group
of proteins that are involved in promoting an apopto-
tic mode of cell death involving DNA fragmentation
and cell shrinkage. Death receptors, such as tumor
necrosis factor-a (TNF-a), on the cell surface can initi-
ate a caspase cascade upon binding of ligands such as
Fas ligand, TNF-a or TNF-related apoptosis-inducing
ligand [3]. Although caspases play a crucial role in cell
death, increasing evidence suggests that cells can turn
on caspase-independent modes of cell death under a
variety of circumstances [4]. Various modes of neuro-
nal death have been described and are commonly
observed in neurodegenerative disorders and stroke [5].

During development, dying neurons display similar
changes in morphology and nuclear DNA degradation
through an apoptotic process, although it has been
suggested that more than one cell death mechanism
may act during development [6]. In addition, both in
development and in neurodegenerative diseases, only
specific sets of neurons die. For example, in Hunting-
ton’s disease, predominantly the striatal neurons
degenerate. In Alzheimer’s disease (AD) and Parkin-
son’s disease (PD), cholinergic neurons in the basal
forebrain and dopaminergic neurons in the nigro-stria-
tal system seem to be particularly vulnerable. What
Keywords
Akt ⁄ PKB; apoptosis; caspase; cell survival;
ERK; ischemia; neurodegenerative disease;
neuronal death; sustained ERK; transient ERK
Correspondence
S. Subramaniam, Solomon H. Snyder
Department of Neuroscience, Johns
Hopkins University School of Medicine,
Baltimore, MD 21205, USA
Fax: +410 955 3623
Tel: +410 955 2379
E-mail:
(Received 19 June 2009, revised 28 August
2009, accept 4 September 2009)
doi:10.1111/j.1742-4658.2009.07367.x
Extracellular signal-regulated kinase (ERK) is a versatile protein kinase
that regulates many cellular functions. Growing evidence suggests that
ERK1 ⁄ 2 plays a crucial role in promoting cell death in a variety of neuro-

nal systems, including neurodegenerative diseases. It is believed that the
magnitude and the duration of ERK1 ⁄ 2 activity determine its cellular func-
tion. In this review, we summarize recent evidence for a role of ERK1 ⁄ 2in
neuronal death. Furthermore, we discuss the mechanisms involved in
ERK1 ⁄ 2 mediating neuronal death.
Abbreviations
AD, Alzheimer’s disease; CDK, cyclin-dependent kinase; CGN, cerebellar granule neurons; EGF, epidermal growth factor; ERK, extracellular
signal-regulated kinase; JNK, c-JunNH
2
-terminal kinase; MAPK, mitogen-activated protein kinase; MCAO, middle cerebral artery occlusion;
NGF, nerve growth factor; PD, Parkinson’s disease; ROS, reactive oxygen species; TNF, tumor necrosis factor.
22 FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS
makes these specific sets of neurons particularly sus-
ceptible to death stimuli and what signaling mecha-
nisms are behind such selective neurodegeneration, are
far from clear. However, an understanding of the
mechanisms of neuronal death is crucial for designing
effective therapeutic strategies for neurodegenerative
diseases.
Mitogen-activated protein kinase
(MAPK) in neuronal death
The MAPKs are serine ⁄ threonine protein kinases that
promote a large diversity of cellular functions in many
cell types. Three major mammalian MAPK subfamilies
have been described: the extracellular signal-regulated
kinases 1 and 2 (ERK1 ⁄ 2), the c-JunNH
2
-terminal kin-
ases (JNK) and the p38 kinases. There is a widely
accepted perception that JNK⁄ SAPK (stress-activated

protein kinase) and p38 MAPK promote cell death,
whereas ERK1 ⁄ 2 opposes cell death [5]. However, this
view is overly simplistic. A growing number of studies
have suggested a death-promoting role for ERK1 ⁄ 2in
both in vitro and in vivo models of neuronal death.
Recently, a new member of MAPKs, ERK5 (also
called big mitogen-activated kinase 1; BMK1) has been
identified and implicated in neuronal survival [7].
Rapid ERK5 activation was observed in the hippo-
campal cornu ammonis (CA3) and dentate gyrus
regions after cerebral ischemia [8]. In medulloblastoma
cell lines, overexpression of ERK5 was shown to
promote apoptotic cell death [9]. Most of the pharma-
cological studies implicating ERK1 ⁄ 2 have been car-
ried out using PD98059 or U0126 (which inhibits
mitogen-activated protein kinase/ERK kinase (MEK),
an upstream activator of ERK1⁄ 2). Both of these
inhibitors also inhibit ERK5 activation [10]. Therefore,
it remains to be seen whether ERK5 is also involved in
ERK1 ⁄ 2-implicated cell death paradigms.
ERK1
⁄
2 in cellular models of neuronal
death
The first evidence for a role of ERK1 ⁄ 2 in cell death
was demonstrated in the oligodendroglial cell line,
CG4. The addition of H
2
O
2

to CG4 cells resulted in
activation of all three major MAPKs. However, H
2
O
2
-
induced cell death was prevented by pharmacological
blockade of the ERK1 ⁄ 2 pathway (PD98059) inhibitor
only [11]. In neuronal cells, glutamate- or camptothe-
cin-induced neuronal injury was abolished when
ERK1 ⁄ 2 activation was suppressed using U0126 inhibi-
tor [12,13]. Neuronal death induced by glutathione
depletion was shown to be abolished when reactive
oxygen species (ROS)-dependent activation of ERK1 ⁄ 2
was inhibited by either PD98059 or U0126 [14]. Nitric
oxide produced by glial cells induced neuronal degener-
ation through ERK1 ⁄ 2 activation that had been
blocked by PD98059 or U0126 [15]. Another recent
study using U0126 showed that death of striatal neu-
rons induced by dopamine was associated with ERK1 ⁄ 2
activation [16]. Death of cortical neurons mediated by
the transient receptor potential vanilloid 1 channel was
abolished when ERK1 ⁄ 2 activation was suppressed by
PD98059 [17]. Ho et al. [18] demonstrated that a zinc-
dependent pathway of cell death is abolished when
ERK1 ⁄ 2 activation is prevented by U0126. Consistent
with a promoting role of ERK1 ⁄ 2 in cell death, hippo-
campal damage after traumatic brain injury was pre-
vented by the inhibition of ERK1 ⁄ 2 by PD98059 [19].
ERK1 ⁄ 2 activation is also implicated in hyperglycemia-

mediated cerebral damage [20]. Similarly, ERK1 ⁄ 2
activation is involved in b-amyloid-induced neuronal
cell death [21]. Thus, ERK1 ⁄ 2 activation seems to play
an active role in several models of neuronal death.
Transient versus sustained ERK1
⁄
2
activation
Mechanisms underlying ERK1 ⁄ 2-mediated neuronal
death are only beginning to emerge. It is challenging to
understand how ERK1 ⁄ 2 can promote either neuronal
survival or neuronal death under different paradigms.
Oxidative stress generated by ROS is often linked to an
activation of the ERK1 ⁄ 2 pathway. ROS-induced
ERK1 ⁄ 2 activation has been demonstrated in a wide
variety of cells, including neurons [22]. Oxidants induce
neuronal death and in several other paradigms discussed
above seem to require a sustained ERK1 ⁄ 2 activation
for promoting neuronal death. Luo and DeFranco [23]
elegantly demonstrated that a transient ERK1 ⁄ 2 activa-
tion induced by glutamate in HT-22 cells reflects a pro-
survival response. In contrast, sustained ERK1 ⁄ 2
activation observed after 6 h of glutamate treatment is a
prodeath signal. Moreover, this study also demonstrated
that sustained ERK1 ⁄ 2 activation alone is not sufficient
to promote HT-22 cell death, implying that ERK1 ⁄ 2
must cooperate with other pathways or cellular compo-
nents affected by glutamate to elicit cell death [23].
Transient ERK1 ⁄ 2 activation has also been observed
upon growth factor stimulation. Brain derived neuro-

trophic factor (BDNF) protects hippocampal neurons
from glutamate toxicity by transient activation of
ERK1 ⁄ 2 [24]. We have demonstrated that insulin-like
growth factor-1 transiently induced ERK1 ⁄ 2, but abro-
gated the induction of a prodeath sustained ERK1 ⁄ 2
signal in cerebellar granule neurons (CGN). We showed
S. Subramaniam and K. Unsicker ERK1 ⁄ 2 in neuronal death
FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS 23
that this inhibition is mediated via the phosphatidylino-
sitol 3-kinase ⁄ protein kinase A ⁄ C-raf pathway [25]. In
addition, we observed that transforming growth factor-
b, a prodeath factor for CGN, also transiently enhanced
ERK1 ⁄ 2 activation in CGN. However, transforming
growth factor-b requires the sustained p38 pathway to
induce CGN cell death [26]. These studies have strength-
ened the notion that both the magnitude and the dura-
tion of ERK1 ⁄ 2 activation determine the cellular
outcomes, and that growth factors may exert regulatory
functions with regard to the death-promoting capacity
of the ERK1 ⁄ 2 pathway.
In PC12 cells it is well known that epidermal growth
factor (EGF) transiently induces ERK1 ⁄ 2 activity,
which stimulates cell growth, whereas nerve growth fac-
tor (NGF)-mediated sustained ERK1 ⁄ 2 activity leads to
neurite outgrowth and cell survival. It has been pro-
posed that this differential effect of ERK1 ⁄ 2 may
depend on the specific receptor availability. It is well
known that EGF receptors are downregulated faster
than NGF receptors upon respective ligand binding. In
addition, stimulation of endogenous EGF receptors

promotes transient ERK1 ⁄ 2 and proliferation, and
EGF receptor overexpression induces sustained ERK1 ⁄
2 and promotion of differentiation. Thus, in PC12 cells,
the duration of ERK1 ⁄ 2 activation seems to depend on
surface receptor availability [27]. However, an implica-
tion of surface receptor availability in regulating
ERK1 ⁄ 2 is not the only mechanism determining the
duration of ERK1 ⁄ 2 activation. For example, macro-
phage migration inhibitory factor can induce sustained
ERK1 ⁄ 2 via Rho and in a Rho kinase-dependent man-
ner [28]. Alternatively, it can induce transient ERK1 ⁄ 2
via Src-type tyrosine kinase [29]. Overactivation of the
EGF receptor in drosophila neurons, or cultured
cortical neurons, leading to activation of the ERK1 ⁄ 2
pathway can promote neuronal degeneration [5]. Thus,
temporal regulation of ERK1 ⁄ 2 not only depends on
receptor availability, but also possibly on differential
regulation of other signaling pathways (Fig. 1).
It is noteworthy that a sustained ERK1 ⁄ 2 activation
does not always promote cell death. As discussed
above, in PC12 cells a sustained ERK1 ⁄ 2 activation
induced by NGF promotes differentiation and cell sur-
vival. Thus, the decision by sustained ERK1 ⁄ 2to
induce cell death or survival possibly depends on addi-
tional factors. NGF, in addition to inducing sustained
ERK1 ⁄ 2, might also activate other parallel signaling
pathways. For example, NGF might activate Akt ⁄ pro-
tein kinase B or ERK5 for cell survival [30,31] and
such prosurvival signals might suppress ERK1 ⁄ 2 cell
death function in PC12 cells, as observed in CGN [25].

In addition, a recent study suggested that sustained
ERK1 ⁄ 2 recruits micro-RNA to promote PC12 cell
survival by blocking the expression of the proapoptotic
BH3-only protein Bcl2-interacting mediator of cell
death (BIM) [32]. Similarly, whether micro-RNA are
involved in ERK1 ⁄ 2-dependent neuronal death is not
known. Thus, sustained ERK1 ⁄ 2 may recruit differen-
tial downstream factors to promote survival or death
through yet unknown mechanisms.
Mechanisms of ERK1
⁄
2-promoted cell
death
Oxidants can activate ERK1 ⁄ 2 either through acting on
receptors, calcium channels, or directly on Src-tyrosine
Fig. 1. Model of ERK1 ⁄ 2 in life and death. Both survival and death
signals can activate ERK1 ⁄ 2. The mechanisms involved in such dif-
ferential ERK1 ⁄ 2 activation and how ERK1 ⁄ 2 interacts with other
cellular components are not yet clear. It is believed that the dura-
tion, magnitude and ⁄ or compartmentalization of active ERK1 ⁄ 2 dic-
tate the cellular outcome. For example, ERK1 ⁄ 2 may be transiently
induced by growth factors, resulting in promotion of neuronal sur-
vival (dotted arrow), whereas oxidative stress may result in a sus-
tained induction of ERK1 ⁄ 2, which may promote neuronal death.
However, for promoting cell death ERK1 ⁄ 2 induction must not
always be sustained. In an MCAO model, ERK1 ⁄ 2 was shown to
be transiently induced, but ERK1 ⁄ 2 inhibition significantly reduced
the ischemic damage. In addition to ERK1 ⁄ 2, death signals can also
activate stress kinases, such as p38 ⁄ JNK, which may further
potentiate neuronal death (thick arrow). On the other hand, survival

signals, such as protein kinase B ⁄ Akt, can inhibit sustained ERK1 ⁄ 2
and thereby promote neuronal survival.
ERK1 ⁄ 2 in neuronal death S. Subramaniam and K. Unsicker
24 FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS
kinase. Activated ERK1 ⁄ 2 can interact with cytoplasmic
components or can translocate to the nucleus. Evidence
has shown that sustained ERK1 ⁄ 2 is translocated to the
nucleus [33,34] and nuclear translocated ERK1 ⁄ 2 can
promote neuronal cell death, regulating transcription
[5,35]. Although caspases have been implicated as pre-
dominant inducers of apoptotic cell death, numerous
studies have shown that apoptotic mechanisms can
operate without the involvement of caspases [36–38].
Several studies have also demonstrated that caspase
activation and the subsequent development of biochemi-
cal or morphological features of apoptotic cell death are
not mutually interdependent. Caspase-independent
pathways can operate to promote apoptotic cell death
and, conversely, cells dying through a nonapoptotic
mode may recruit caspase-dependent pathways [5]. In
the CGN model of neuron death, we observed activa-
tion and nuclear translocalization of ERK1 ⁄ 2 after
withdrawal of the survival signal. This sustained
ERK1 ⁄ 2 activation promoted plasma membrane dam-
age, whereas caspase-3 activation observed in a subset
of CGN promoted DNA damage [34]. Biochemical and
morphological features of plasma membrane-damaged
CGN resembled neither necrosis nor apoptosis, but
rather represented a mixture of apoptotic and necrotic
features, including plasma membrane damage and apop-

totic-like nuclear condensation. This ‘necro-apoptotic’
mode of neuron death could not be blocked by caspase
inhibitors.
Thus, ERK1 ⁄ 2 seems to play a crucial role in pro-
moting this unique kind of cell death independent of
caspase activation [34]. Similarly, ERK1 ⁄ 2 was shown
to promote neuronal death in several other models
independently of caspase. Thus, substance P and its
receptor, neurokinin-1, mediate an alternative, nona-
poptotic form of cell death in hippocampal, striatal
and cortical neurons via ERK1 ⁄ 2 activation [39,40].
17beta-E2, a steroid hormone, induces oncotic ⁄ necro-
tic, but not apoptotic, programmed cell death in a sub-
population of developing granule cells by activating
the ERK1 ⁄ 2 pathway [41]. Okadaic acid-induced death
of pyramidal cells in the CA3 region, which was not
consistent with apoptotic features, is dependent on
ERK1 ⁄ 2 activation [42]. In addition, it was demon-
strated that neurotrophin-aggravated necrotic neuronal
death was mediated by ERK1 ⁄ 2 [43]. Together, these
data suggest that ERK1 ⁄ 2-mediated features of neuro-
nal death may differ depending on cell type and death
stimulus, but in several cell death models, ERK1 ⁄ 2
seems to promote predominantly a nonapoptotic mode
of death independently of caspases. The identity of the
molecular players associated with ERK1 ⁄ 2 in caspase-
independent neuronal death still remains to be estab-
lished [44].
Whether ERK1 ⁄ 2 directly activates cell death path-
ways or whether it changes the prodeath gene expres-

sion profile is not completely understood. Sustained
ERK1 ⁄ 2 was shown to translocate to the nuclei, sug-
gesting it may regulate prodeath gene expression
[33,34]. When sustained ERK1 ⁄ 2 is retained in the
cytoplasm, neuronal death is no longer observed, sug-
gesting a requirement of nuclear retention for prodeath
function [33]. On the other hand, in non-neuronal
cells, cytoplasmic retention of ERK1 ⁄ 2 is required for
death-associated protein kinase-mediated cell death
[35]. Thus, ERK1 ⁄ 2 might promote cell death depend-
ing upon the cell type. Considering the fact that
ERK1 ⁄ 2 has multiple activators and targets, it is possi-
ble that activation and its cell death-promoting func-
tion may involve multiple partners and regulations [5].
ERK1
⁄
2 in neurodegeneration and
ischemia
ERK1 ⁄ 2-induced neuronal degeneration has also been
extended to various models of neurodegenerative dis-
ease. In AD, phosphorylated ERK1 ⁄ 2 immunoreactiv-
ity in a granular appearance has been described in a
subpopulation of hippocampal neurons with neurofi-
brillary degeneration [45]. Tau, a microtubule-associ-
ated protein, and its abnormal hyperphosphorylation
have been linked to neuronal death in AD [46].
ERK1 ⁄ 2 is known to regulate tau hyperphosphoryla-
tion [47,48], and it has been reported that activation
of ERK1 ⁄ 2 in AD links oxidative stress to abnormal
tau phosphorylation [45]. In addition, an upregulation

of ERK1 ⁄ 2 has been shown to be associated with the
progression of neurofibrillary degeneration in AD [49].
Considering that the mode and the mechanism of
neuronal death in AD has not been fully resolved as
yet [50], it is conceivable that ERK1 ⁄ 2 might play a
crucial role in yet incompletely understood mecha-
nisms of tau-mediated AD pathology. Furthermore,
b-amyloid-induced sustained ERK1 ⁄ 2 activation has
been shown to contribute to b-amyloid-induced tau
phosphorylation and neurite degeneration [51].
6-Hydroxy-dopamine (OHDA) and MPTP, neurotoxins
commonly used in animal models of PD, have been
shown to induce cell death through ERK1 ⁄ 2 activation
[52,53]. More recently, granular cytoplasmic aggregates
of activated ERK1 ⁄ 2 have been observed in the substan-
tia nigra of PD patients with Lewy bodies [54]. Neuronal
cell-specific cyclin-dependent kinase 5 (CDK5), a known
regulator of neurodegenerative disorders such as AD
and PD, can be a direct target for ERK1 ⁄ 2. Studies with
S. Subramaniam and K. Unsicker ERK1 ⁄ 2 in neuronal death
FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS 25
non-neuronal cells have suggested that ERK1 ⁄ 2 can
regulate CDKs [55]. For example, ERK1 ⁄ 2 mediates
DNA damage-induced breast cancer cell death via
CDK5 regulation [56]. Whether CDKs are involved
in ERK1 ⁄ 2-mediated death of neuronal cells is not
known.
ERK1 ⁄ 2 activation also plays a major role in ische-
mia-induced cell death. Alessandrini et al. [57] have
demonstrated a transient activation of ERK1 ⁄ 2 in the

middle cerebral artery occlusion (MCAO) model. Inhi-
bition of ERK1 ⁄ 2 activation reduced the infarct size
by 55% compared with the control. Various other
groups have reported an involvement of ERK1 ⁄ 2in
MCAO, hypoxia–ischemia and other ischemic models
[58–61]. ERK1 ⁄ 2 activation has also been reported in
permanent MCAO [62], although the causal link
between ERK1 ⁄ 2 activation and neuronal death still
has to be proven in this model of permanent MCAO.
So far, only the temporal pattern of activation of
ERK1 ⁄ 2 in permanent MCAO suggests a role for
ERK1 ⁄ 2 in neuronal death [63,64].
Conclusions and perspectives
Initially, ERK1 ⁄ 2 activation was considered as a pro-
moter of neuronal survival and memory [65–67]. How-
ever, it is now clear that ERK1 ⁄ 2 activation can also
participate in a variety of neuronal death signals. Such
differential functions can be attributed to the duration
of ERK1 ⁄ 2 signaling and association with other
molecular players [68,69]. This association may elicit a
unique pattern of molecular organization and may also
result in a differential gene expression profile, which
consequently results in different cellular functions. The
opposing roles of ERK1 ⁄ 2 activation are perhaps best
illustrated by its implication in the protection of CGN
survival in N-methyl-d-aspartate-mediated excito-
toxicty and its association with cortical neuron death
following glutamate exposure [12,70]. Thus, the stimu-
lus, the cell type and, probably most importantly, the
duration of the activation of ERK1 ⁄ 2 decide the life

or death of neurons.
The opposing roles of ERK1 ⁄ 2 in neuron survival
and death make it difficult to exploit it for cell survival
strategies. Even so, the application of ERK1 ⁄ 2 inhibi-
tors to prevent ischemic damage in preclinical trials is
under debate [71]. Similarly, inhibition of ERK1 ⁄ 2
(MEK inhibitor, PD184352) to block proliferation has
been shown to be effective in clinical trials in cancer
patients [72]. Therefore, understanding the detailed sig-
naling mechanisms of the diverse and opposing func-
tions of ERK1 ⁄ 2 is paramount for designing strategies
that can specifically attenuate ERK1 ⁄ 2-promoted
neuronal pathologies without affecting other ERK1 ⁄ 2
functions.
Acknowledgement
The work described in this article was supported by
the Deutsche Forschungsgemeinschaft (DFG) grant
Un34 ⁄ 23-1.
References
1 Andrabi SA, Dawson TM & Dawson VL (2008)
Mitochondrial and nuclear cross talk in cell death:
parthanatos. Ann NY Acad Sci 1147, 233–241.
2 Leadsham JE & Gourlay CW (2008) Cytoskeletal
induced apoptosis in yeast. Biochim Biophys Acta 1783,
1406–1412.
3 Lorz C & Mehmet H (2009) The role of death receptors
in neural injury. Front Biosci 14, 583–595.
4 Tait SW & Green DR (2008) Caspase-independent cell
death: leaving the set without the final cut. Oncogene
27, 6452–6461.

5 Subramaniam S & Unsicker K (2006) Extracellular
signal-regulated kinase as an inducer of non-apoptotic
neuronal death. Neuroscience 138, 1055–1065.
6 Johnson EM Jr & Deckwerth TL (1993) Molecular
mechanisms of developmental neuronal death. Annu
Rev Neurosci 16, 31–46.
7 Cavanaugh JE (2004) Role of extracellular signal regu-
lated kinase 5 in neuronal survival. Eur J Biochem 271,
2056–2059.
8 Wang RM, Zhang QG, Li CH & Zhang GY (2005)
Activation of extracellular signal-regulated kinase 5
may play a neuroprotective role in hippocampal
CA3 ⁄ DG region after cerebral ischemia. J Neurosci Res
80, 391–399.
9 Sturla LM, Cowan CW, Guenther L, Castellino RC,
Kim JY & Pomeroy SL (2005) A novel role for extra-
cellular signal-regulated kinase 5 and myocyte enhancer
factor 2 in medulloblastoma cell death. Cancer Res 65,
5683–5689.
10 Nishimoto S & Nishida E (2006) MAPK signalling:
ERK5 versus ERK1 ⁄ 2. EMBO Rep 7, 782–786.
11 Bhat NR & Zhang P (1999) Hydrogen peroxide activa-
tion of multiple mitogen-activated protein kinases in an
oligodendrocyte cell line: role of extracellular signal-reg-
ulated kinase in hydrogen peroxide-induced cell death.
J Neurochem 72, 112–119.
12 Stanciu M, Wang Y, Kentor R, Burke N, Watkins S,
Kress G, Reynolds I, Klann E, Angiolieri MR, Johnson
JW et al. (2000) Persistent activation of ERK1 ⁄ 2 con-
tributes to glutamate-induced oxidative toxicity in a

neuronal cell line and primary cortical neuron cultures.
J Biol Chem 275, 12200–12206.
ERK1 ⁄ 2 in neuronal death S. Subramaniam and K. Unsicker
26 FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS
13 Lesuisse C & Martin LJ (2002) Immature and mature
cortical neurons engage different apoptotic mechanisms
involving caspase-3 and the mitogen-activated protein
kinase pathway. J Cereb Blood Flow Metab 22, 935–
950.
14 de Bernardo S, Canals S, Casarejos MJ, Solano RM,
Menendez J & Mena MA (2004) Role of extracellular
signal-regulated protein kinase in neuronal cell death
induced by glutathione depletion in neuron ⁄ glia me-
sencephalic cultures. J Neurochem 91, 667–682.
15 Canals S, Casarejos MJ, de Bernardo S, Solano RM &
Mena MA (2003) Selective and persistent activation of
extracellular signal-regulated protein kinase by nitric
oxide in glial cells induces neuronal degeneration in glu-
tathione-depleted midbrain cultures. Mol Cell Neurosci
24, 1012–1026.
16 Chen J, Rusnak M, Lombroso PJ & Sidhu A (2009)
Dopamine promotes striatal neuronal apoptotic death
via ERK1 ⁄ 2 signaling cascades. Eur J Neurosci 29, 287–
306.
17 Shirakawa H, Yamaoka T, Sanpei K, Sasaoka H,
Nakagawa T & Kaneko S (2008) TRPV1 stimulation
triggers apoptotic cell death of rat cortical neurons.
Biochem Biophys Res Commun 377, 1211–1215.
18 Ho Y, Samarasinghe R, Knoch ME, Lewis M,
Aizenman E & DeFranco DB (2008) Selective inhibition

of mitogen-activated protein kinase phosphatases by
zinc accounts for extracellular signal-regulated kinase
1 ⁄ 2-dependent oxidative neuronal cell death. Mol
Pharmacol 74, 1141–1151.
19 Lu KT, Cheng NC, Wu CY & Yang YL (2008)
NKCC1-mediated traumatic brain injury-induced brain
edema and neuron death via Raf ⁄ MEK ⁄ MAPK cas-
cade. Crit Care Med 36, 917–922.
20 Zhang JZ, Jing L, Guo FY, Ma Y & Wang YL (2007)
Inhibitory effect of ketamine on phosphorylation of the
extracellular signal-regulated kinase 1 ⁄ 2 following brain
ischemia and reperfusion in rats with hyperglycemia.
Exp Toxicol Pathol 59, 227–235.
21 Frasca G, Carbonaro V, Merlo S, Copani A & Sortino
MA (2008) Integrins mediate beta-amyloid-induced cell-
cycle activation and neuronal death. J Neurosci Res 86,
350–355.
22 Hidalgo C & Nunez MT (2007) Calcium, iron and neu-
ronal function. IUBMB Life 59, 280–285.
23 Luo Y & DeFranco DB (2006) Opposing roles for
ERK1 ⁄ 2 in neuronal oxidative toxicity: distinct mecha-
nisms of ERK1 ⁄ 2 action at early versus late phases of
oxidative stress. J Biol Chem 281, 16436–16442.
24 Almeida RD, Manadas BJ, Melo CV, Gomes JR, Men-
des CS, Graos MM, Carvalho RF, Carvalho AP &
Duarte CB (2005) Neuroprotection by BDNF against
glutamate-induced apoptotic cell death is mediated by
ERK1 ⁄ 2 and PI3-kinase pathways. Cell Death Differ
12, 1329–1343.
25 Subramaniam S, Shahani N, Strelau J, Laliberte C,

Brandt R, Kaplan D & Unsicker K (2005) Insulin-like
growth factor 1 inhibits extracellular signal-regulated
kinase to promote neuronal survival via the phosphati-
dylinositol 3-kinase ⁄ protein kinase A ⁄ c-Raf pathway.
J Neurosci 25, 2838–2852.
26 Subramaniam S, Strelau J & Unsicker K (2008)
GDNF prevents TGF-beta-induced damage of the
plasma membrane in cerebellar granule neurons by
suppressing activation of p38-MAPK via the phospha-
tidylinositol 3-kinase pathway. Cell Tissue Res 331,
373–383.
27 Marshall CJ (1995) Specificity of receptor tyrosine
kinase signaling: transient versus sustained extracellular
signal-regulated kinase activation. Cell 80, 179–185.
28 Swant JD, Rendon BE, Symons M & Mitchell RA
(2005) Rho GTPase-dependent signaling is required for
macrophage migration inhibitory factor-mediated
expression of cyclin D1. J Biol Chem 280, 23066–23072.
29 Lue H, Kapurniotu A, Fingerle-Rowson G, Roger T,
Leng L, Thiele M, Calandra T, Bucala R & Bernhagen
J (2006) Rapid and transient activation of the ERK1 ⁄ 2
MAPK signalling pathway by macrophage migration
inhibitory factor (MIF) and dependence on
JAB1 ⁄ CSN5 and Src kinase activity. Cell Signal 18,
688–703.
30 Virdee K, Xue L, Hemmings BA, Goemans C,
Heumann R & Tolkovsky AM (1999) Nerve growth
factor-induced PKB ⁄ Akt activity is sustained by
phosphoinositide 3-kinase dependent and independent
signals in sympathetic neurons. Brain Res 837, 127–142.

31 Kamakura S, Moriguchi T & Nishida E (1999) Activa-
tion of the protein kinase ERK5 ⁄ BMK1 by receptor
tyrosine kinases. Identification and characterization of a
signaling pathway to the nucleus. J Biol Chem 274,
26563–26571.
32 Terasawa K, Ichimura A, Sato F, Shimizu K &
Tsujimoto G (2009) Sustained activation of ERK1 ⁄ 2by
NGF induces microRNA-221 and 222 in PC12 cells.
FEBS J 276, 3269–3276.
33 Stanciu M & DeFranco DB (2002) Prolonged nuclear
retention of activated extracellular signal-regulated pro-
tein kinase promotes cell death generated by oxidative
toxicity or proteasome inhibition in a neuronal cell line.
J Biol Chem 277, 4010–4017.
34 Subramaniam S, Zirrgiebel U, von Bohlen Und
Halbach O, Strelau J, Laliberte C, Kaplan DR &
Unsicker K (2004) ERK1 ⁄ 2 activation promotes
neuronal degeneration predominantly through plasma
membrane damage and independently of caspase-3.
J Cell Biol 165, 357–369.
35 Mebratu Y & Tesfaigzi Y (2009) How ERK1 ⁄ 2 acti-
vation controls cell proliferation and cell death: is
subcellular localization the answer? Cell Cycle 8,
1168–1175.
S. Subramaniam and K. Unsicker ERK1 ⁄ 2 in neuronal death
FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS 27
36 Cummings BS & Schnellmann RG (2002) Cisplatin-
induced renal cell apoptosis: caspase 3-dependent
and -independent pathways. J Pharmacol Exp Ther 302,
8–17.

37 Belmokhtar CA, Hillion J & Segal-Bendirdjian E (2001)
Staurosporine induces apoptosis through both caspase-
dependent and caspase-independent mechanisms. Onco-
gene 20, 3354–3362.
38 Volbracht C, Leist M, Kolb SA & Nicotera P (2001)
Apoptosis in caspase-inhibited neurons. Mol Med 7,
36–48.
39 Castro-Obregon S, Del Rio G, Chen SF, Swanson RA,
Frankowski H, Rao RV, Stoka V, Vesce S, Nicholls
DG & Bredesen DE (2002) A ligand–receptor pair that
triggers a non-apoptotic form of programmed cell
death. Cell Death Differ 9, 807–817.
40 Castro-Obregon S, Rao RV, del Rio G, Chen SF, Pok-
say KS, Rabizadeh S, Vesce S, Zhang XK, Swanson
RA & Bredesen DE (2004) Alternative, nonapoptotic
programmed cell death: mediation by arrestin 2,
ERK1 ⁄ 22, and Nur77. J Biol Chem 279, 17543–17553.
41 Wong JK, Le HH, Zsarnovszky A & Belcher SM
(2003) Estrogens and ICI182,780 (Faslodex) modulate
mitosis and cell death in immature cerebellar neurons
via rapid activation of p44 ⁄ p42 mitogen-activated
protein kinase. J Neurosci 23, 4984–4995.
42 Runden E, Seglen PO, Haug FM, Ottersen OP, Wieloch
T, Shamloo M & Laake JH (1998) Regional selective
neuronal degeneration after protein phosphatase inhibi-
tion in hippocampal slice cultures: evidence for a MAP
kinase-dependent mechanism. J Neurosci 18, 7296–7305.
43 Lobner D & Liot G (2004) Role of MAPK ⁄ ERK1 ⁄ 2in
neurotrophin-4 potentiation of necrotic neuronal death.
Neurochem Res 29, 2303–2309.

44 Cande C, Cecconi F, Dessen P & Kroemer G (2002)
Apoptosis-inducing factor (AIF): key to the conserved
caspase-independent pathways of cell death? J Cell Sci
115, 4727–4734.
45 Perry G, Roder H, Nunomura A, Takeda A, Friedlich
AL, Zhu X, Raina AK, Holbrook N, Siedlak SL,
Harris PL et al. (1999) Activation of neuronal extra-
cellular receptor kinase (ERK1 ⁄ 2) in Alzheimer disease
links oxidative stress to abnormal phosphorylation.
Neuroreport 10, 2411–2415.
46 Shahani N, Subramaniam S, Wolf T, Tackenberg C &
Brandt R (2006) Tau aggregation and progressive neu-
ronal degeneration in the absence of changes in spine
density and morphology after targeted expression of
Alzheimer’s disease-relevant tau constructs in organo-
typic hippocampal slices. J Neurosci 26, 6103–6114.
47 Guise S, Braguer D, Carles G, Delacourte A & Briand
C (2001) Hyperphosphorylation of tau is mediated by
ERK1 ⁄ 2 activation during anticancer drug-induced
apoptosis in neuroblastoma cells. J Neurosci Res 63,
257–267.
48 Harris FM, Brecht WJ, Xu Q, Mahley RW & Huang Y
(2004) Increased tau phosphorylation in apolipoprotein
E4 transgenic mice is associated with activation of
extracellular signal-regulated kinase: modulation by
zinc. J Biol Chem 279, 44795–44801.
49 Pei JJ, Braak H, An WL, Winblad B, Cowburn RF,
Iqbal K & Grundke-Iqbal I (2002) Up-regulation of
mitogen-activated protein kinases ERK1 ⁄ 2 and
MEK1 ⁄ 2 is associated with the progression of neurofi-

brillary degeneration in Alzheimer’s disease. Brain Res
Mol Brain Res 109, 45–55.
50 Jellinger KA & Stadelmann C (2001) Problems of cell
death in neurodegeneration and Alzheimer’s disease.
J Alzheimers Dis 3 , 31–40.
51 Rapoport M & Ferreira A (2000) PD98059 prevents
neurite degeneration induced by fibrillar beta-amyloid
in mature hippocampal neurons. J Neurochem 74,
125–133.
52 Kulich SM & Chu CT (2001) Sustained extracellular
signal-regulated kinase activation by 6-hydroxydop-
amine: implications for Parkinson’s disease. J Neuro-
chem 77, 1058–1066.
53 Gomez-Santos C, Ferrer I, Reiriz J, Vinals F,
Barrachina M & Ambrosio S (2002) MPP+ increases
alpha-synuclein expression and ERK1 ⁄ 2 ⁄ MAP-kinase
phosphorylation in human neuroblastoma SH-SY5Y
cells. Brain Res 935, 32–39.
54 Zhu JH, Kulich SM, Oury TD & Chu CT (2002)
Cytoplasmic aggregates of phosphorylated extracellular
signal-regulated protein kinases in Lewy body diseases.
Am J Pathol 161, 2087–2098.
55 Meloche S & Pouyssegur J (2007) The ERK1 ⁄ 2
mitogen-activated protein kinase pathway as a master
regulator of the G1- to S-phase transition. Oncogene 26,
3227–3239.
56 Upadhyay AK, Ajay AK, Singh S & Bhat MK (2008)
Cell cycle regulatory protein 5 (Cdk5) is a novel down-
stream target of ERK1 ⁄ 2 in carboplatin induced death
of breast cancer cells. Curr Cancer Drug Targets 8,

741–752.
57 Alessandrini A, Namura S, Moskowitz MA & Bonven-
tre JV (1999) MEK1 protein kinase inhibition protects
against damage resulting from focal cerebral ischemia.
Proc Natl Acad Sci USA 96, 12866–12869.
58 Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T,
Chan PH, Trzaskos JM & Feuerstein GZ (2003) Signifi-
cant neuroprotection against ischemic brain injury by
inhibition of the MEK1 protein kinase in mice: explora-
tion of potential mechanism associated with apoptosis.
J Pharmacol Exp Ther 304, 172–178.
59 Noshita N, Sugawara T, Hayashi T, Lewen A, Omar G
& Chan PH (2002) Copper ⁄ zinc superoxide dismutase
attenuates neuronal cell death by preventing extracellular
signal-regulated kinase activation after transient focal
cerebral ischemia in mice. J Neurosci 22, 7923–7930.
ERK1 ⁄ 2 in neuronal death S. Subramaniam and K. Unsicker
28 FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS
60 Cho DG, Mulloy MR, Chang PA, Johnson MD,
Aharon AS, Robison TA, Buckles TL, Byrne DW &
Drinkwater DC Jr (2004) Blockade of the
extracellular signal-regulated kinase pathway by
U0126 attenuates neuronal damage following
circulatory arrest. J Thorac Cardiovasc Surg 127,
1033–1040.
61 Wang Z, Chen X, Zhou L, Wu D, Che X & Yang G
(2003) Effects of extracellular signal-regulated kinase
(ERK1 ⁄ 2) on focal cerebral ischemia. Chin Med J
(Engl) 116, 1497–1503.
62 Kitagawa H, Warita H, Sasaki C, Zhang WR, Sakai K,

Shiro Y, Mitsumoto Y, Mori T & Abe K (1999) Immu-
noreactive Akt, PI3-K and ERK1 ⁄ 2 protein kinase
expression in ischemic rat brain. Neurosci Lett 274,
45–48.
63 Irving EA, Barone FC, Reith AD, Hadingham SJ &
Parsons AA (2000) Differential activation of
MAPK ⁄ ERK1 ⁄ 2 and p38 ⁄ SAPK in neurones and glia
following focal cerebral ischaemia in the rat. Brain
Res Mol Brain Res 77, 65–75.
64 Lennmyr F, Karlsson S, Gerwins P, Ata KA & Terent
A (2002) Activation of mitogen-activated protein kinas-
es in experimental cerebral ischemia. Acta Neurol Scand
106, 333–340.
65 Fukunaga K & Miyamoto E (1998) Role of MAP
kinase in neurons. Mol Neurobiol 16, 79–95.
66 Grewal SS, York RD & Stork PJ (1999) Extracellular-
signal-regulated kinase signalling in neurons. Curr Opin
Neurobiol 9, 544–553.
67 Sweatt JD (2004) Mitogen-activated protein kinases in
synaptic plasticity and memory. Curr Opin Neurobiol
14, 311–317.
68 Corbit KC, Foster DA & Rosner MR (1999) Protein
kinase Cdelta mediates neurogenic but not mitogenic
activation of mitogen-activated protein kinase in neuro-
nal cells. Mol Cell Biol 19, 4209–4218.
69 York RD, Yao H, Dillon T, Ellig CL, Eckert SP,
McCleskey EW & Stork PJ (1998) Rap1 mediates sus-
tained MAP kinase activation induced by nerve growth
factor. Nature 392, 622–626.
70 Zhu D, Wu X, Strauss KI, Lipsky RH, Qureshi Z,

Terhakopian A, Novelli A, Banaudha K & Marini AM
(2005) N-methyl-D-aspartate and TrkB receptors pro-
tect neurons against glutamate excitotoxicity through an
extracellular signal-regulated kinase pathway. J Neuro-
sci Res 80, 104–113.
71 Irving EA & Bamford M (2002) Role of mitogen- and
stress-activated kinases in ischemic injury. J Cereb
Blood Flow Metab 22, 631–647.
72 Allen LF, Sebolt-Leopold J & Meyer MB (2003)
CI-1040 (PD184352), a targeted signal transduction
inhibitor of MEK (MAPKK). Semin Oncol 30, 105–
116.
S. Subramaniam and K. Unsicker ERK1 ⁄ 2 in neuronal death
FEBS Journal 277 (2010) 22–29 ª 2009 The Authors Journal compilation ª 2009 FEBS 29