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.. ERK1 ⁄ 2
Trang 1ERK and cell death: ERK1 ⁄2 in neuronal death
Srinivasa Subramaniam1and Klaus Unsicker2
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: ssubram9@jhmi.edu
(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⁄ 2 in 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.
Trang 2makes 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-JunNH2-terminal
kin-ases (JNK) and the p38 kinkin-ases 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⁄ 2 in
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 H2O2 to CG4 cells resulted in
activation of all three major MAPKs However, H2O2
-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
Trang 3that 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⁄ 2 to
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.
Trang 4kinase 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 morphologibiochemi-cal 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 translocalizaactiva-tion 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 apoptonecro-tic, 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 Considerdepend-ing 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 regulafunc-tions [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 activahyperphosphoryla-tion
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
Trang 5non-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⁄ 2 in
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
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