ERK1/2 as a transducer of extrinsic survival signals The first reported experiments suggesting that ERK1/2 maytransduce anti-apoptotic signaling in neurons were performed in neuronallydif
Trang 1M I N I R E V I E W
Role of extracellular signal regulated kinases 1 and 2 in neuronal survival
Michal Hetman1,2,3 and Agata Gozdz1
1
Kentucky Spinal Cord Research Injury Center and Departments of Neurological Surgery and2Pharmacology and Toxicology, University of Louisville, KY, USA;3Nencki Institute, Warsaw, Poland
Extracellular signal regulated kinases 1 and 2 (ERK1/2)
regulate cellular responses to a varietyof extracellular
stimuli In the nervous system, ERK1/2 is critical for
neur-onal differentiation, plasticityand mayalso modulate
neuronal survival In this minireview, we present evidence
that supports prosurvival activityof ERK1/2 in neurons
Several reports suggest that ERK1/2 mediates
neuropro-tective activityof extracellular factors, including
neurotro-phins In addition, ERK1/2 is activated byneuronal injury
In damaged cells, ERK1/2 activation mayact as a defensive
mechanism that helps to compensate for the deleterious effects of a damaging insult The emerging mechanisms of ERK1/2-mediated neuroprotection mayinvolve transcrip-tional regulation and/or direct inhibition of cell death machinery
Keywords: apoptosis; MAP-kinase; neurons; neuropro-tection; programmed cell death; signal transduction; survival
Signaling pathways and neuronal survival
Death of neurons occurs during development of the central
nervous system (CNS) Therefore, restriction of neuronal
death bysurvival signaling is critical for the proper
formation of the CNS [1] In CNS pathologies including
stroke, Alzheimer’s disease or CNS trauma, nerve cell death
occurs as a result of cell injury[1] Consequently, survival
signaling cascades mayprovide targets for neuroprotective
therapies against these conditions Neuronal survival
sign-aling involves several pathways including
phoshpatidylo-inositol-3-kinase (PI3K), extracellular signal regulated
kinase 1/2 (ERK1/2) or extracellular signal regulated
kin-ase 5 (ERK5) [2] Interestingly, while PI3K seems to be
the principal transducer for prosurvival factors involved
in trophic support, several reports suggest preferential
ERK1/2 involvement in protection against damage-induced
cell death Therefore, manipulations of the latter pathway
maybe useful for neuroprotective interventions in diseases
ERK1/2 signaling
ERK1, also known as p44 mitogen activated protein kinase (MAP kinase), and ERK2 (p42 MAP kinase) are closely related protein kinases of the MAP kinase family[3] ERK1/2
is regulated bya cascade of phosphorylations including
a dual phosphorylation at Thr/Tyr residues of the ERK1/2 activation domain that is carried out byMAP kinase kinase 1/2 (MKK1/2) [3] These dual phosphorylation events activate ERK1/2 [3] MKK1/2 is, in turn, activated by phosphorylation catalyzed by the Raf family of protein kinases Raf activators include small GTPases, Ras or Rap3 ERK1/2 activityis decreased byeither phosphotyrosine phosphatases or dual specificity(Ser/Thr + Tyr) phospha-tases known as MAP kinase phosphaphospha-tases (MKPs) [3] ERK1/2 is considered a Ôproline directed kinaseÕ as it phosphorylates Ser or Thr residues followed by a proline ERK1/2 targets include several transcription factors, sign-aling mediators, cytoskeletal proteins and protein kinases [3] ERK1/2 mayalso engage in the regulation of cellular processes via protein–protein interactions rather than through its kinase activity For instance, kinase dead mutant forms of ERK2 mayactivate MKPs or DNA topoiso-merase II [3] It is believed that ERK1/2 interactions with its activators and/or substrates are enhanced byscaffolding proteins such as MP-1 [3] Also, ERK1/2 signaling maybe regulated bysubcellular localization [3] and crosstalk to other signaling mediators including Ca2+, cAMP or PI3K [2,4] Biological processes involving ERK1/2 include stimu-lation of cell proliferation and survival, neoplastic transfor-mation, neuronal differentiation and plasticity[2,3]
Tools to study ERK1/2 signaling
Several approaches have been employed to study the biological role of ERK1/2 in mammalian cells including
Correspondence to Michal Hetman, KentuckySpinal Cord
Research InjuryCenter, Universityof Louisville, 511 S Floyd St.,
MDR616, Louisville, KY 40292, USA.
Fax: + 1 502 852 5148, Tel.: + 1 502 852 3619,
E-mail: michal.hetman@louisville.edu
Abbreviations: BDNF, brain derived neurotrophic factor; CNS,
cen-tral nervous system; CREB, cAMP response element binding protein;
ERK, extracellular signal regulated kinase; HSV2, herpes simplex
virus type 2; MAP, mitogen activated protein; MKK1/2, MAP kinase
kinase 1/2; MKP, MAP kinase phosphatase; NGF, nerve growth
factor; NMDA, N-methyl- D -aspartate; NMDAR, NMDA receptor;
P13K, phoshpatidyloinositol-3-kinase; PARP,
poly-(ADP-ribose)-polymerase; TGFa, transforming growth factor a.
(Received 14 February2004, accepted 18 March 2004)
Trang 2overexpression of mutated elements of the pathway, use of
pharmacological inhibitors and genetic ablation in
knock-out mice [3] Perhaps the most popular tools to manipulate
ERK1/2 signaling are the dominant-negative and the
constitutive-active mutants of MKK1 as well as several
pharmacological inhibitors of MKK1/2 It is important to
realize the limitations of these tools First, it is possible that
MKK1/2 mayalso have other targets than ERK1/2 [5]
Secondly, specificityof commonlyused MKK1/2 drug
inhibitors is not absolute For instance, PD98059 and
U0126 mayinhibit signaling byERK5 [6] PD98059 was
also shown to directlyinhibit cyclooxygenases [7] and block
Ca2+influx into isolated synaptosomes [8] The
interpret-ation of the data obtained through experimental
modula-tion of ERK1/2 signaling maybe hampered bythe fact that
inhibition of one element of the ERK1/2 signaling network
maymodulate other signaling units For instance, selective
inhibition of MKK1/2 increases ERK5 activity[6]
There-fore, the optimal design of experiments addressing ERK1/2
function could include application of several inhibitors and
dominant-negative mutants that act at various levels of the
ERK1/2 cascade as well as testing the effects of these agents
on other signaling circuitries that maycrosstalk to ERK1/2
ERK1/2 as a transducer of extrinsic survival
signals
The first reported experiments suggesting that ERK1/2
maytransduce anti-apoptotic signaling in neurons were
performed in neuronallydifferentiated PC12 cells [9]
Because nerve growth factor (NGF) activated ERK1/2
in this system, and NGF withdrawal-induced apoptosis
was prevented byoverexpression of constitutivelyactive
mutants of MKK1, Xia et al proposed that trophic
signaling byNGF was mediated through the ERK1/2
pathway[9] Additional studies showed that ERK1/2
activation mayalso block cell death induced bytrophic
deprivation of retinal ganglion cells, cerebellar granule
neurons or spiral ganglion neurons In rat retinal ganglion
cells or cerebellar granule neurons, protective ERK1/2 was
activated bybrain derived neurotrophic factor (BDNF)
[10–12], or bycAMP signaling triggered byPACAP or
forskolin [10,13] In rat spiral ganglion neurons, ERK1/2
mediated the protective effect of the neuromodulator
substance P [14] However, several other studies using
both pharmacological inhibitors and various mutants of
the ERK1/2 pathwaysuggested that ERK1/2 maynot be
the major mediator of neuroprotection afforded
byneuro-trophins, IGF-1 or membrane depolarization in
trophic-deprived neurons (reviewed in [2]) Importantly, as the
studies indicating a lack of ERK1/2 involvement in
antiapoptotic signaling used a varietyof neuronal cells,
the role of ERK1/2 in protection against trophic
with-drawal mayappear onlyin some contexts In contrast,
PI3K/Akt signaling seems to be the principal mediator of
both the anti-apoptotic effects of basal trophic support and
neuroprotective action of agents that suppress trophic
deprivation-induced cell death [2]
Although the contribution of ERK1/2 to support
neur-onal survival under ÔbasalÕ culture conditions maybe
minimal, there is accumulating evidence that ERK1/2 may
mediate the neuroprotective activityof such factors that
neuroprotect against damaging insults For instance, ERK1/2 activation byBDNF was shown to protect cultured rat cortical neurons against apoptosis induced by DNA damage [15,16] In these studies, DNA damage was induced bygenotoxic anticancer drugs, camptothecin or cisplatin (CPDD) Interestingly, cisplatin is highly neuro-toxic, which limits its use against CNS tumors [17] BDNF protection against neuronal apoptosis induced byeither of these compounds was inhibited with MKK1/2 blockers, PD98059 or SL327 (a blood–brain barrier permeable compound similar to U0126) Because neurons that over-expressed a constitutive-active form of MKK1 were protected against camptothecin or CPDD, it seems that ERK1/2 activation is both necessaryand sufficient for the anti-apoptotic action of BDNF [15,16] Similarly, Anderson
& Tolkovskyshowed that in cultured sympathetic neurons exposed to another DNA-damaging agent, cytosine arabi-noside, PD98059 inhibited NGF-mediated protection, implicating ERK1/2 involvement [18]
There are several reports suggesting that ERK1/2 may serve as a transducer for agents that protect from other forms of neuronal injuryincluding excitotoxicity, calcium overload, oxidative injury, hypoxia or neurotoxic viruses ERK1/2 is required for neuroprotection byestrogen against glutamate excitotoxicity[19] Also, in hippocam-pal slice cultures that were challenged byan excitotoxic insult with N-methyl-D-aspartate (NMDA), the protective effects of nicotine were ERK1/2-dependent [20] In another study, transforming growth factor a (TGFa) was shown to protect neurons from NMDA-induced death byactivating astrocytic ERK1/2 In agreement with the anti-excitotoxic effects of ERK1/2, cortical neuron death byionomycin-induced Ca2+ overload was attenuated byBDNF, at least in part, via ERK1/2 activation [21]
ERK1/2 also seems to contribute to the neuroprotective effects of cAMP For instance, corticotrophin releasing hormone protected hippocampal slices from excitotoxicity bycAMP-mediated activation of ERK1/2 [22] Also, prostaglandin E1, a signaling mediator know to activate the cAMP pathway, protected rat spinal neurons against nitric oxide, acting partiallythrough ERK1/2 [23] Similarly, the cAMP inducer forskolin increased the survival of cultured dopaminergic neurons byreducing the sponta-neous oxidative toxicity, via stimulation of the ERK1/2 pathway[24]
ERK1/2 activation mediates the protective effects of several factors that enhance neuronal survival in hypoxia/ ischemia models For instance, Han & Holtzman showed that in P7 rat pups, intraventrical injection of BDNF protected against hypoxic/ischemic brain injury through ERK1/2 but not PI3K [25] Other examples of neuropro-tectants that counteract hypoxia by activating ERK1/2 include erythropoietin, fructose-1, 6-biphosphate or N-acetyl-o-methyldopamine [26–28] Finally, TGF1b-medi-ated ERK1/2 activation inhibited staurosporine-induced cell death of cultured hippocampal neurons and was also suggested to protect in a rat stroke model [29] An interesting example of ERK1/2-mediated neuroprotection against injuryis that induced bythe herpes simplex virus type 2 (HSV2) In this case, virally produced ICP10 protein activated ERK1/2 to inhibit apoptosis of infected
Trang 3hippocampal neurons [30] Thus, ERK1/2 appears to be
required for several neuroprotectants that support neuronal
survival after injury
Activation of ERK1/2 as a defense mechanism
in neuronal injury
Neurons respond to cell damage byactivation of death
signaling pathways However, at the same time, cells may
also mobilize defense mechanisms in an attempt to
coun-teract cell death and enable damage repair Interestingly,
defensive ERK1/2 activation is observed after neuronal
injuries ERK1/2 activation was observed in cultured
cortical or hippocampal neurons exposed to the DNA
damaging agents, camptothecin, CPDD or etoposide
[15,16,31] In cultured rat cortical neurons, CPDD-mediated
activation of ERK1/2 reached levels similar to those
observed at the peak of BDNF action [16] Inhibition
of ERK1/2 byeither pharmacological inhibitors or bya
dominant-negative mutant form of MKK1 increased
CPDD-induced apoptosis and further reduced survival of
CPDD-treated neurons [16] Surprisingly, the protective
ERK1/2 activation turned out to be mediated byNMDA
receptors (NMDARs) [16] Further experiments indicated
that in CPDD-treated neurons, NMDAR signaling to
ERK1/2 is enhanced byactivation of
poly-(ADP-ribose)-polymerase (PARP), an enzyme that mobilizes DNA repair
but mayalso lead to energetic deprivation and necrosis [16]
Elevated PARP activitywas suggested to stimulate
NMDAR signaling bydepleting neurons of ATP [32]
Because the moderate increase in PARP activityobserved in
CPDD-treated neurons did not deplete cellular ATP, PARP
contribution to the defensive ERK1/2 activation mayresult
from a mechanism that does not involve disturbed neuronal
energetics [16] Therefore, it appears that DNA damage by
CPDD mayactivate a novel neuronal defense circuitrythat
engages PARP, NMDAR and ERK1/2 It remains to be
tested if a similar pathwaymaycontribute to the defense
against other genotoxic insults The role of ERK1/2 in
neuronal survival after exposure to DNA-damaging
anti-cancer agents suggests that neurotoxicityinduced during
cancer treatment maybe enhanced bydrugs affecting
protective ERK1/2 activation including the clinicallyused
NMDAR antagonist, memantine
ERK1/2 seems to be an important defense mechanism
against hypoxia/ischemia Induction of ischemic tolerance
byan episode of mild ischemia can be modeled in cultured
rat cortical neurons bytransient oxygen/glucose
depriva-tion [33] Gonzalez-Zulueta et al showed that in this
system, protective oxygen/glucose deprivation
precondi-tioning activated NMDARs resulting in increased
produc-tion of NO and subsequent activaproduc-tion of Ras, which
ultimatelysignaled to ERK1/2 [33] The inhibition of
ERK1/2 activation in this case completelyabolished the
protective effects of preconditioning [33] Furthermore,
in mouse cortical neurons that were exposed to cytotoxic
hypoxia, ERK1/2 was activated and ERK1/2 pathway
blockers increased hypoxia-induced cell death [34]
ERK1/2 mayalso playa role in neuronal protection in
status epilepticus Inhibition of ERK1/2 activation with
SL327 increased mortalityin rats with pilocarpine-induced
seizures [35]
Interestingly, in several non-neuronal systems, damaging stimuli including DNA injury, oxidative stress or death receptor signaling were reported to mobilize an anti-apoptotic ERK1/2 activity[36–38] These data suggest an interesting possibilitythat ERK1/2 activation maybe a general defense mechanism that is mobilized to protect different cell types against various forms of damage
Protective mechanisms downstream
of ERK1/2
The ERK1/2 pathwayaffects multiple targets that may mediate its prosurvival activity These include transcription factors that could stimulate production of anti-apoptotic mediators or inhibit accumulation of killer proteins In addition, ERK1/2 mayalso directlyaffect several cell death/ cell survival regulators The protective mechanisms that do not involve gene expression maybe particularlyrelevant for the survival of damaged neurons, under conditions where gene expression machineryis disturbed
In the nervous system, protective ERK1/2 signaling may target both gene dependent and gene expression-independent events (Fig 1) For instance, Bonni et al suggested that activation of a transcription factor, cAMP response element binding protein (CREB) and/or a direct inhibition of Bad, a pro-apoptotic member of the bcl-2 family, maymediate the prosurvival activityof ERK1/2 in trophic-deprived cerebellar granule neurons [12] In this study, ERK1/2 appeared to mediate its effects through direct action on its target kinase, p90Rsk2 Inhibition of Rsk2 with a dominant-negative mutant blocked ERK1/2-mediated inhibition of apoptosis Also, the prosurvival activityof ERK1/2 was reduced byantagonizing the Rsk target CREB In addition, a dominant-negative mutant form of Rsk2 decreased the anti-apoptotic phosphorylation
of Bad at its Ser112 residue Finally, Rsk2 activation by ERK1/2 protected against apoptosis that was induced byan overexpressed wild type, but not a Ser112fi Ala mutant form of Bad InhibitoryBad phosphorylation is also implicated as a mechanism of prosurvival ERK1/2 activity
in neurons exposed to damage In cultured hippocampal neurons that were protected against staurosporine-induced apoptosis byTGFb1, ERK1/2 stimulated survival by
Fig 1 Neuroprotective mechanisms employed by ERK1/2 Bold italic indicates the targets whose regulation byERK1/2 appears to be gene expression-dependent ERK1/2-mediated inhibition of Bim may involve both inhibitoryphosphory lation and decreased expression Dotted lines indicate prosurvival ERK1/2 targets that were found in non-neuronal systems and may also be involved in neuroprotection See text for more details.
Trang 4Rsk-mediated phosphorylation of Bad Ser112 [29]
More-over, in murine brain, TGFb1 protected against ischemia
while activating ERK1/2 and increasing Bad
phosphoryla-tion at Ser112 [29] This same ERK/Rsk-mediated
phos-phorylation event also occurred in cultured mouse cortical
neurons that were exposed to a neuroprotective hypoxia
treatment [34]
In neuronallydifferentiated PC12 cells, the anti-apoptotic
protection with NGF was suggested to be a result of
ERK1/2-mediated inhibition of another pro-apoptotic
member of the bcl-2 family, Bim40 The increase in Bim
expression was implicated as one of the killer mechanisms
activated byNGF withdrawal in this system If
trophic-deprived cells were rescued with NGF, Bim protein levels
decreased This effect was mediated bythe ERK1/2
pathway[39] Furthermore, ERK1/2 activation induced
Bim phosphorylation at Ser109 and Thr110 residues that
inhibited apoptosis induced bythe overexpressed Bim40
Therefore, it appears that the ERK1/2 pathwaymayinhibit
Bim function both bythe decrease in Bim expression and by
the direct phosphorylation of Bim
Neuroprotection byERK1/2 mayalso involve a
CREB-mediated increase in the expression of anti-apoptotic
members of the bcl-2 familyincluding bcl-2 and bag-1
For instance, the prosurvival activityof ERK1/2 in PC12
cells mayproceed via CREB-stimulated expression of bcl-2
[40] Furthermore, in HSV2-infected neurons, apoptosis was
suppressed byan ERK1/2-dependent increase of bag-1
expression [30] that was presumed to be CREB-mediated
Similarly, overexpression of the endogenous CREB
antag-onist ICER induced apoptosis and decreased bcl-2 levels in
cultured rat cortical neurons [41] Finally, ERK1/2 may
protect from neuronal death byinhibiting the activityof a
pro-apoptotic kinase GSK3b [42]
Neuroprotective mechanisms controlled byERK1/2 may
also involve indirect effects in non-neuronal CNS cells
including glia and vascular cells For instance, Gabriel et al
have shown that in mixed cortical cultures, neurons were
protected from NMDA-mediated
excitotoxicitybyTGFa-induced ERK1/2 activation in astrocytes [43] In these cells,
ERK1/2 increased production of type 1 inhibitor of tissue
type plasminogen activator that blocked the neurotoxic
activityof a secreted protease, tissue-type plasminogen
activator Interestingly, Notch3 protects against ischemic
stroke bysupporting survival of brain vascular smooth
muscle cells [44] Notch3 mediated protection is suggested
to occur through an ERK1/2-dependent up-regulation of
c-FLIP that subsequentlyblocks the pro-apoptotic
activa-tion of caspase 8 [44]
Outside the nervous system, there are several interesting
observations pointing to the possible modes of
ERK1/2-mediated neuroprotection Allan et al found that ERK2
can directlyphosphorylate caspase 9 at Thr125 [45] This
phosphorylation event blocked caspase 9-mediated
activa-tion of caspase 3 [45] Indeed, there are reports suggesting
that ERK1/2 mayprotect byinhibiting apoptosis
down-stream of cytochrome c release, one of the keysteps directly
linked to caspase activation in the mitochondrial death
pathway[46,47]
Another example of an interesting anti-apoptotic
ERK1/2 target is a protein encoded bythe Drosophila head
involution defective (Hid) gene Hid activates Drosophila
caspases and mammalian caspase 8 [48,49] Activityof this protein is inhibited through a direct phosphorylation by ERK1/2 [48] Intriguingly, caspase 8 activation by death receptor signaling was blocked through ERK1/2 [38] This inhibition was independent of protein synthesis indicating that a Hid-like ERK1/2 target mayexist in mammals [38] Noteworthy, in cardiomiocytes, ERK1/2 protected against cell death bythe upregulation of cyclooxygenase-2 gene transcription and the resulting increase in production of cytoprotective prostaglandins [36]
A functional proteomics approach revealed several candidate ERK1/2 signaling substrates that mayparticipate
in neuroprotection [50] For instance, ERK1/2 activation targeted an anti-apoptotic member of the bcl-2 family, mcl-1 and also DNA repair enzymes of the nucleotide excision repair pathway[50] The significance of these ERK1/2 signaling substrates for neuronal survival remains
to be elucidated Lastly, ERK1/2 activation may be beneficial for functional recoveryfollowing CNS injuryin the absence of eliciting anyeffects on the survival of damaged neurons For instance, ERK1/2 mayenhance proliferation of neural stem cells that mayreplace the deceased neurons [51] ERK1/2 mayalso contribute to the functional plasticityafter traumatic brain injury[52]
In conclusion, dissection of the protective mecha-nisms activated byERK1/2 in the nervous system is still incomplete
ERK1/2: Killer or savior?
There are several reports summarized in the accompanying review byChu et al that ERK1/2 inhibition protects neurons in ischemia, traumatic brain injury, epilepsy or oxidative glutamate toxicity[53] How does one reconcile these observations with the proposed protective role of ERK1/2? Interestingly, several signaling systems have also been recognized to have seeminglycontradictoryeffects on cellular survival For instance, NMDAR can trigger cell death but mayalso have protective effects [54] Likewise, the tumor suppressor protein p53 can trigger apoptosis but mayalso enhance DNA repair and cell survival [55] The factors that are proposed to determine the beneficial or deleterious outcome of these multifunctional transducers include differences in the activation intensityor duration, the subcellular localization of signaling molecules, the signaling context provided byother pathways or the cellular energetic state Importantly, the nature and extent
of cellular injurymayalso change the ultimate results of the same signaling events Finally, chronic activation of a signaling pathwaymaylead to an increased activityof inhibitoryfeedback pathways switching off downstream signaling that is normallyactivated bythis circuitry Some
or all of these factors mayalso affect the ultimate outcome
of ERK1/2 activation in the nervous system A number of these issues are further discussed in the accompanying review byChu et al with a particular focus on neuro-degeneration [53]
Perspectives
In summary, it appears that in many cases ERK1/2 activation is neuroprotective and mediates the effects of
Trang 5several extrinsic survival signals Furthermore, ERK1/2
activation is found in injured neurons where, at least in
some cases, it has the protective, compensatoryrole The
neuroprotective mechanisms controlled byERK1/2 include
regulation of pro- and anti-apoptotic members of the bcl-2
family It is probable that other mediators underlying
prosurvival activityof ERK1/2 in neurons will be uncovered
in the future The factors that determine whether ERK1/2
activation will stimulate or inhibit neuronal survival will
also be an interesting target for research Identification of
these factors maybe critical for the development of useful
strategies for targeting the ERK1/2 cascade to intervene
against neurological diseases
Acknowledgements
This work was supported bya NIH/NCRR grant, RR15576 The
authors wish to thank Drs Richard Benton, Scott R Whittemore,
Donald DeFranco and Jane E Cavanaugh for critical reading of this
paper.
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