IUBMB Life, 58(11): 621 631, November 2006
Critical Review
ERK1/2 MAP Kinases in Cell Survival and Apoptosis
Zhimin Lu1 and Shuichan Xu2
1
Brain Tumor Center and Departments of Neuro-Oncology and Molecular Genetics, The University of Texas M. D.
Anderson Cancer Center, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas,
USA
2
Signal Pharmaceuticals, LLC, 4550 Towne Centre Ct., San Diego, California, USA
Summary
ERK1/2 is an important subfamily of mitogen-activated protein
kinases that control a broad range of cellular activities and
physiological processes. ERK1/2 can be activated transiently or
persistently by MEK1/2 and upstream MAP3Ks in conjunction with
regulation and involvement of scaolding proteins and phospha-
tases. Activation of ERK1/2 generally promotes cell survival; but
under certain conditions, ERK1/2 can have pro-apoptotic functions.
IUBMB Life, 58: 621631, 2006
Keywords ERK1/2; cell survival; apoptosis.
INTRODUCTION: MAP KINASE PATHWAYS AND THEIR
SPECIFICITY
With a total of 518 members identied in the human genome,
protein kinases are one of the largest gene families in eukaryotes
(1 3). Mutation and dysregulation of protein kinases play
causal roles in human disease and provide a basis for developing
agonists and antagonists of these enzymes for therapy. Acting as
serine and threonine protein kinases, mitogen-activated protein
(MAP) kinases comprise a family of protein kinases whose
function and regulation have been conserved evolutionarily,
from unicellular organisms like yeast to complex organisms
such as humans (4). By phosphorylating specic serines and
threonines of target protein substrates, MAP kinases regulate a
wide range of processes: cell growth and dierentiation, gene
expression, mitosis, cell motility, metabolism, cell survival and
apoptosis, and embryogenesis (5, 6).
The classic MAP kinase family consists of three sub-
families: extracellular signal-regulated kinase (ERK; ERK1
and ERK2), c-Jun N-terminal kinase (JNK; JNK1, JNK2,
and JNK3), and p38-MAP kinase (a, b, d, and g). In addition,
Received 27 April 2006; accepted 14 August 2006
Address correspondence to: Zhimin Lu, The University of Texas
M. D. Anderson Cancer Center, Houston, TX 77030, USA.
E-mail: zhiminlu@mdanderson.org
ISSN 1521-6543 print/ISSN 1521-6551 online 2006 IUBMB
DOI: 10.1080/15216540600957438
ERK 3 to 8 have been identied, although their function and
regulation are less well characterized (7). The MAP kinase
signaling pathway is a three-tiered cascade: a MAP kinase is
activated by a MAP kinase kinase (MKK or MAP2K), which
is in turn activated by a MAP kinase/ERK kinase (MEK)
kinase or MAP kinase kinase kinase (MEKK or MAP3K)
(8, 9) (Fig. 1). In mammalian cells, 12 MAP kinases, 7
MAP2Ks, and 20 MAP3Ks have been identied. MAP kinases
are activated by dual phosphorylation on a conserved Thr-
Xaa-Tyr motif in their activation loop by an upstream
MAP2K. MAP2Ks are themselves activated by phosphoryla-
tion via an upstream MAP3K (10). In addition to the
predominant mode of MAP kinase activation by MAP2K-
mediated dual phosphorylation, MAP2K-independent activa-
tion of p38 MAP kinase has been reported. Transforming
growth factor b-activated protein kinase 1 (TAK1)-binding
protein 1 (TAB1), a scaolding protein, binds to p38a-MAP
kinase and stimulates autophosphorylation of its Thr-Gly-Tyr
motif, resulting in the initiation of kinase activity indepen-
dently of MKK3 and MKK6 (11).
Each of the MAP kinase families can be activated by at
least two cognate MAP2Ks and by multiple MAP3Ks.
MAP2Ks display remarkable substrate specicity for their
MAP kinases; several recognize only one or two MAP kinases
and few if any other substrates. In contrast, MAP3Ks can
activate multiple MAP kinase cascades (10) (Fig. 1). The
multiple mammalian MAP3Ks, MAP2Ks, and MAPKs form
distinct signal transduction pathways and complexes of signal-
ing molecules in response to dierent extracellular stimuli. The
dierent combinations of these three tiers of kinases give rise to
the signaling specicity. For example, the MAP3K TAK1 is
indispensable for activation of JNK in response to the pro-
inammatory molecule lipopolysaccharide (LPS), whereas the
expression of four MAP3Ks is required for osmotic stress-
induced JNK activation (12). The signaling specicity is also
controlled by regulation of scaolding proteins, which can
sequester and insulate signaling components and direct them to
622 LU AND XU

specic subcellular localizations, enhancing the signal ux
and mediating cross-talk with other pathways (13).
MAP kinases directly interact with scaolding proteins,
activators, and eectors, and these interactions also govern
signaling specicity. MAP kinases have a docking groove
comprised of an acidic common docking (CD) domain and
Glu-Asp (ED) pockets that are distinct from their active sites
(14, 15). The interacting proteins, such as MAP kinase
substrates, MAP2Ks, phosphatases, and scaolds, have a
docking (D) domain (DEJL motif-docking site for ERK and
JNK, also known as Leu-X-Leu motif) that complements the
MAP kinase binding motifs. The D domain is composed of
basic and hydrophobic residues with the consensus sequence
Arg/Lys2-Xaa2 6-Faa-Xaa-Faa (where Faa represents the
hydrophobic residues Leu, Ile, and possibly Val) (14, 16, 17).
In addition to the D domain, many substrates of ERK and
p38aMAP kinase have the DEF (docking site for ERK, also
known as FXF) binding motif, which consists of two Phe
residues separated by one residue and is often followed by a
Pro residue (FXFP) (18 20). This docking motif binds to a
hydrophobic pocket in the large lobe of the MAP kinase
adjacent to its catalytic domain. The DEF motif is within 10
residues COOH-terminal to the site of phosphorylation on the
substrate, which corresponds to the distance between the
hydrophobic region and the catalytic sites in ERK2 (21).
Unlike the D domain of substrates that can bind to active and
inactive MAP kinase, the DEF motif only binds to active
ERK2 molecules, because the DEF binding site on ERK is
exposed only upon ERK2 phosphorylation (21, 22). Thus, the
substrate specicity and binding anity are controlled by the
interaction between the phosphoacceptor motif, the D
domain, and the DEF motif in substrates and the correspond-
ing catalytic area, docking groove, and DEF binding region on
a MAP kinase (Fig. 2). In summary, the functional

Figure 1. Conventional (ERK1/2, JNK, and p38-MAP kinase) and ERK5 MAP kinase signaling pathways in mammalian cells
and in yeast. Only representative signaling molecules are shown. Solid arrows indicate main pathways, and dashed arrows
indicate branched pathways and indirect activation. MAPK, MAP kinase.

Figure 2. Representative schematic interactions between ERK2 and ERK2 substrates such as Elk1. The phosphoacceptor motif,
the D domain, and the DEF motif in ERK substrates interact with the corresponding catalytic area, docking groove, and DEF
binding region in ERK2.
 ROLE OF ERK1/2 MAP KINASES IN CELLS
consequence of MAP kinase signaling activation is determined
by dierent combinations of the three tiers of kinases;
regulation and involvement of distinct scaolding proteins;
and selective interaction between the MAP kinase and its
binding proteins, such as MAP kinase substrates, MAP2Ks,
phosphatases, and scaolding proteins.
ANTI-APOPTOTIC AND PRO-APOPTOTIC FUNCTIONS
OF ERK1/2 MAP KINASES
Overview of ERK1/2
ERK1 and ERK2 are 83% identical with most of the
dierences falling outside the kinase core (23). ERK1/2 is
expressed in all tissues. In broblasts, it is activated by growth
factors, serum, ligands that stimulate heterotrimeric G
protein-coupled receptors, cytokines, transforming growth
factors, osmotic stress, and microtubule disorganization (5).
Conventionally, ERK1/2 is activated by a cascade comprised
of a small G protein Ras-Raf family member (Raf-1, A-Raf,
B-Raf) followed by MEK1/2. Nevertheless, Ras is not the only
activator upstream of Raf for regulating ERK1/2. Protein
kinase C (PKC) a has been shown to phosphorylate and
activate Raf-1 (13). Mixed lineage kinase 3 (MLK3) is
required for mitogen-stimulated phosphorylation of B-Raf at
Thr598 and Ser601, and this phosphorylation is required for
B-Raf activation and subsequently ERK1/2 activation (24).
Similarly, Raf is not the only MAP3K for regulating ERK1/2.
Mos (25), TPL2 protooncogene (26), MLK-like mitogen-
activated protein triple kinase (MLTK) (27), and interleukin-1
(IL-1) receptor-associated kinase (IRAK) (28) have been
reported to function as MAP3Ks to activate ERK1/2.
Overexpression of MEKK1, MEKK2, or MEKK3, which
are MAP3Ks that primarily regulate the JNK pathway,
activates ERK1/2 indirectly through MEK1/2 (29 33). Thus,
ERK1/2 can be activated by distinct MAP3Ks and MAP3K
upstream activators in response to dierent stimuli.
ERK1/2 preferentially phosphorylates substrates that con-
tain the consensus sequence Pro-Xaa-Ser/Thr-Pro, whereby
the Pro residue is conserved at the P1 position and the Pro
residue at the P-2 position is less conserved (34). A Pro residue
at position P-1 can reduce the eciency of phosphorylation
(35). The activation of ERK1/2, induced by dierent initiating
signals, results in the phosphorylation of dierent substrates;
thus far, more than 150 substrates have been identied. These
substrates can be categorized as transcription factors, protein
kinases, protein phosphatases, cytoskeletal proteins, scaold-
ing proteins, receptors, signaling molecules, apoptosis-related
proteins, as well as other types of proteins (Table 1) (22).
The roles of ERK1 and ERK2 in embryogenesis have been
illustrated by the study of ERK1/2 decient mice. ERK17/7
mice are viable, fertile, and of normal size (36). However,
thymocyte maturation beyond the CD4CD8 stage is
reduced in these mice, and the thymocyte subpopulation
expressing high levels of T cell receptor is similarly decreased,
623
which indicates that ERK1 has a specic role in thymocyte
development (36). ERK1-decient mice exhibit a dramatic
enhancement in striatum-dependent long-term memory, cor-
relating with facilitation of long-term potentiation in the
nucleus accumbens (37). Stimulus-dependent ERK2 signaling
is increased in ERK17/7 mice suggesting that upregulation
of ERK2 occurs in the absence of ERK1 (37). In contrast to
the dispensable role of ERK1 in embryonic development that
may be due to ERK2 compensating for a deciency in ERK1,
ERK2-decient embryos fail to form mesoderm (38), the
ectoplacental cone, and extra-embryonic ectoderm giving rise
to the fetal part of the placenta and the secondary trophoblast
giant cells (39, 40). A severe defect in the development of the
placenta is likely an important cause of embryonic lethality
(39). Thus, ERK1 and ERK2 each have distinct roles in
physiological and developmental processes.
Anti-apoptotic Functions of ERK1/2
Activation of ERK1/2 has been shown to inhibit apoptosis
in response to a wide range of stimuli, such as tumor necrosis
factor (TNF), Fas ligand, TNF-related apoptosis-inducing
ligand (TRAIL) (41), radiation (42, 43), osmotic stress (33, 44,
45), hypoxia (46), growth factor withdrawal (47), nitric oxide
(48), hydrogen peroxide (49), matrix detachment (50), and
chemotherapeutic agents (51). In response to most of these
stimuli, ERK1/2 undergoes either transient or prolonged
activation, resulting in an anti-apoptotic eect. In contrast,
inhibition of ERK1/2 promotes apoptosis. The anti-apoptotic
eect can be diminished after prolonged stimulation, because
ERK1/2 activity can be downregulated by dephosphorylation
or degradation of ERK1/2. In response to osmotic stress,
ERK1/2 is activated and increases its binding to MEKK1
E3 ligase through the CD domain. Disruption of this
binding by mutating the ERK2 CD domain sustains ERK2
activation by reduced ubiquitination and degradation of
ERK2. Ubiquitination-resistant ERK2 with a mutant CD
domain has an anti-apoptotic eect against osmotic stress-
induced apoptosis (33). Thus, prevention of downregulation of
ERK1/2 activity can promote cell survival.
The anti-apoptotic eect of ERK1/2 can be regulated
indirectly by p38 signaling (52 54). Inhibition of p38 MAPK
stimulates Raf and ERK activities and induces myoblast
proliferation (52). Activation of p38 results in rapid depho-
sphorylation of MEK1/2 and subsequent apoptosis in human
skin broblasts, whereas inhibition of p38 activity potently
inhibits MEK1/2 dephosphorylation and apoptosis (53).
Furthermore, PP2A has been found in association with
MEK1/2 and ERK1/2 in cardiac ventricular myocytes.
Inhibition of p38 MAPK blocked the ERK-associated PP2A
activity accompanied with enhanced ERK1/2 activity and
attenuated apoptosis in response to H2O2 stimulation (54).
The mechanism by which ERK1/2 activation inhibits
apoptosis is complicated and varies, depending on the cell
and tissue type involved and the cellular regulatory inuences
624 LU AND XU

Table 1
ERK substrates*
Transcription Kinases and Cytoskeletal Signaling Apoptotic proteins
factors phosphatases proteins proteins and proteinases Other proteins

AML1 (RUNX1) DAPK Annexin XI EGFR Bad Amphiphysin 1

Androgen receptor ERK1/2 Caldesmon ENaCb/g Bim-EL CPSII/CAD
ATF2 FAK1 Calnexin Fe65 Calpain CR16
BCL6 GRK2 CENP-E FRS2 Caspase 9 GRASP55
BMAL1 Inhibitor-2 Connexin-43 Gab1 EDD GRASP65
CBP Lck Cortactin Gab2 IEX1 HABP1
C/EBPb MAPKAP3 Crystallin GAIP MCL-1 Histone H
CRY1/2 MAPKAP5 DOC1R Grb10 TIS2 HnRNP-K
E47 MEK1/2 Dystrophin IRS1 TNFR CD120a KIP
Elk1 MKP1/2 Lamin B2 LAT MBP
ER81 MKP3 MAP1 LIFR PHAS-I (4E-BP1)
ERF MKP7 MAP2 MARCKS CPLA2
Estrogen receptor MLCK MAP4 Naf1a Rb
c-Fos MNK1/2 MISS PDE4 SAP90/PSD95
Fra1 MSK1/2 NF-H PLCb Spinophilin
GATA1/2 PAK1 NF-M PLCg Topoisomerase II
HIF1a PTP2C Paxillin Potassium Tpr
HSF1 Raf1 Stathmin channel Kv 4.2 TTP (Nup47)
ICER B-Raf SWI/SNF KSR1 Tyrosine hydroxylase
c-Jun RSK1-4 Synapsin 1 Rab4 Vif
Microphthalmia S6K Tau SH2-B Vpx
c-Myc Syk Vinexin b ShcA
N-Myc Sos1
Net (Sap2) Spin90
NFATc4 TSC2
NF-IL6
NGFI-B/TR3/Nur77
Pax6
PPARg
P53
Progesterone receptor
RNA Pol. II
PUNX2
Sap1
Smad1
Smad2/3
SP1
SRC1
SREBP1/2
STAT1/3
STAT5a
TAL1/SCL
TFII-I
TFIIIB
TGIF
TIF1A
Tob
UBF

*The more detailed information and more compressive references are available in reference (21).
 ROLE OF ERK1/2 MAP KINASES IN CELLS
that the cell receives. In Drosophila, MAPK promotes cell
survival by phosphorylation and inhibition of the pro-
apoptotic protein head involution defective (Hid) (55), which
activates caspases without involvement of mitochondrial
factors (56). In the mammalian cell lines, ERK1/2 signaling
can block apoptosis at levels upstream, downstream, or
unrelated to change of mitochondrial transmembrane poten-
tial and cytochrome c release (47, 57, 58). Activation of
ERK1/2 by constitutive expression of MEK1, or T cell
activation via T cell receptor stimulation, inhibits caspase 8
activation/Bid cleavage and the loss of mitochondrial mem-
brane potential induced by ionizing radiation or activation of
Fas/CD95, TNF, and TRAIL receptors (41, 58, 59). The
inactivation of pro-apoptotic Bcl-2 family member BAD is
mediated through phosphorylation at Ser112 by ERK-
activated p90 ribosomal S6 kinase (RSK) (60) and at
Ser136 by phosphoinositol 3-kinase/AKT signaling. BAD
phosphorylation at serine 112 by RSK suppresses BAD-
mediated neuronal apoptosis, and inhibition of either ERK1/
2 or AKT increases the extent of apoptosis (61 64). The
ERK-downstream p70 S6 kinase may also be involved in
Ser136 phosphorylation and inhibition of BAD function (65).
Nerve growth factor (NGF) actively down-regulates the
expression of another pro-apoptotic Bcl-2 family member,
Bim, via a MEK-ERK1/2 dependent pathway (66). In
addition, NGF promotes rapid MEK-ERK1/2-dependent
phosphorylation of Bim at Ser109 and Thr110, thereby
compromising the apoptotic activity of Bim. Thus, MEK-
ERK1/2 inhibits Bim activity through two distinct mechan-
isms: phosphorylation of Bim and downregulation of Bim
protein expression (66).
In addition to suppressing the functions of pro-apoptotic
proteins, ERK1/2 can promote cell survival by enhancing
the activity of anti-apoptotic molecules. Mcl-1, an anti-
apoptotic member of the Bcl-2 family, is phosphorylated at
Thr163 by ERK1/2, thus increasing its stability and
enhancing its anti-apoptotic activity (67). IEX-1, an early
response and nuclear factor kappa B (NF-kB) target gene,
interacts with phosphorylated ERK1/2 and is phosphorylated
by ERK1/2 primarily at Thr18 (68). Upon phosphorylation
by ERK1/2, IEX-1 acquires the ability to prevent the
release of cytochrome c from mitochondria and to inhibit
cell death induced by cytokine deprivation and stimula-
tion with staurosporine, TNF, or etoposide. In addition to
acting as an ERK1/2 downstream eector mediating
survival, IEX-1 functions as a regulator of ERK1/2 by
enhancing ERK1/2 activation in response to various growth
factors (68).
Evidence has shown that ERK1/2 also functions down-
stream of cytochrome c release. Overexpression of B-Raf,
which does not interfere with the release of cytochrome c from
mitochondria, confers MEK1/2 activity-dependent resistance
to apoptosis induced by growth factor withdrawal or PI
3-kinase inhibition; however, the addition of cytochrome c to
625
cytosols of cells overexpressing B-Raf fails to induce caspase
activation (47). More direct evidence of inhibited activation of
caspases downstream of cytochrome c has been provided by
demonstration that caspase-9 is regulated by ERK1/2 (56).
Caspase-9 is inhibited by phosphorylation at Thr125 in a
MEK1/2-dependent manner in cells stimulated with epidermal
growth factor (EGF) or 12-O-tetradecanoylphorbol-13-
acetate (TPA). Phosphorylation at Thr125, a conserved
MAP kinase consensus site targeted by ERK2 in vitro, is
sucient to block caspase-9 processing and subsequent
caspase-3 activation (69).
In addition to regulating the activity of survival and
apoptotic signaling molecules, ERK1/2 can provide an anti-
apoptotic eect by up- or down-regulating the protein
expression of such molecules. Exogenous expression of
activated Raf-1 enhances the expression of c-Flip, an
endogenous antagonist of caspase-8, in a MEK1/2-dependent
manner (70). Inhibition of ERK1/2 activity causes arrest at
the G1 phase of the cell cycle and downregulation of the
expression levels of Mcl-1 and Bcl-XL, which are the anti-
apoptotic homologs of Bcl-2 (71, 72). Increased expression
and activity of DNA repair proteins, such as excision repair
cross-complementing 1 (ERCC1) and X-ray cross-comple-
menting group 1 (XRCC1), in response to ionizing radiation
have also been found to be dependent upon MEK1/2 activity
(73, 74). Furthermore, ERK1/2 facilitates DNA repair by
regulating the activity of ataxia-telangiectasia mutated
(ATM) and Rad3-related kinase (ATR) (75). By activating
ERK1/2 via MEK1, hydroxyurea induces MEK-ERK1/2
dependent S-phase arrest, which can be attenuated by
inhibition of ERK1/2 activation and thereby sensitize cells
to hydroxyurea-induced toxicity. Blocking ERK1/2 activa-
tion with MEK inhibitors downregulates ATR function by
reducing the redistribution of ATR from the cytosol to the
nucleus and the magnitude of formation of ATR nuclear foci
(75).
ERK1/2 controls cell survival or apoptosis by regulating
the activity of anti- and pro-apoptotic transcription factors.
ERK-activated RSK phosphorylates the transcription factor
cAMP response element-binding protein (CREB) at serine 133
(61), which allows recruitment of the co-activators CREB-
binding protein (CBP) and p300 and strongly enhances
CREB-dependent transcription (76). ERK1 can also directly
phosphorylate CBP in vitro and increase the transcriptional
activity of CBP (77). Activated CREB promotes cell survival,
and inhibition of CREB phosphorylation at serine 133 triggers
neuronal apoptosis (61). In addition, it has been also shown
that inhibition of ERK1/2 upregulates STAT3/5 phosphoryla-
tion and promotes cell apoptosis (78).
In summary, ERK1/2 can provide anti-apoptotic eects
(Fig. 3) by downregulating pro-apoptotic molecules via a
decrease in their activity or a reduction of their protein
expression by transcriptional repression. ERK1/2 can also
promote cell survival by upregulating anti-apoptotic molecules
626 LU AND XU

Figure 3. ERK1/2 regulation in their anti-apoptotic function. ERK1/2 activity is positive regulated by MEK1/2 phosphorylation
and negatively regulated by MEKK1-mediated ubiquitination and p38-dependent PP2A activation.

via enhancement of their activity or activation of their

transcription.

Pro-apoptotic Functions of ERK1/2

Although ERK1/2 is a pro-survival factor in the MAP
kinase family and contributes to the regulation of cell
proliferation and dierentiation, under some circumstances,
ERK1/2 can function in a pro-apoptotic manner (Fig. 4). In
the neuronal system, ERK1/2 has been suggested to be
involved in neurodegeneration (79). Inhibition of MEK1/2
confers protection against neuronal cell death induced by the
toxin 6-hydroxydopamine (80). Persistent activation of ERK1/
2 is associated with glutamate-induced oxidative toxicity in
neuronal cells, and inhibition of ERK1/2 activation protects
cells from glutamate toxicity (81). MEK1 inhibition also
results in reduced brain damage and reduced focal infarct
volume in mice after ischemia, which suggests that the MEK1-
ERK1/2 pathway contributes to brain injury during focal
cerebral ischemia (82, 83). In addition, ERK1/2 activation
promotes low potassium-induced neuronal degeneration pre-
dominantly through plasma membrane damage, which occurs Figure 4. Activation of ERK1/2 in response to some DNA
independently of caspase-3 (84). damage stimuli promotes cell apoptosis by enhancing activity
DNA damaging stimuli, including etoposide, adriamycin, of some pro-apoptotic signaling molecules.
platinum compounds, ionizing irradiation, and ultraviolet
irradiation (UV), activate ERK1/2 in primary cells and adriamycin, platinum compounds, or UV. Conversely,
various cell lines (85, 86). Inhibition of ERK1/2 activation enforced activation of ERK1/2 by overexpression of a
attenuates apoptosis or G2-M arrest induced by etoposide, constitutively activated MEK1 Q56P mutant sensitizes cells
 ROLE OF ERK1/2 MAP KINASES IN CELLS
to DNA damage-induced apoptosis (85). Suppression of
ERK2 activity has been reported to sensitize ovarian
carcinoma cells to cisplatin-induced apoptosis (87, 88), but
it has also been reported to induce drug resistance of cervical
carcinoma cells to cisplatin (89, 90) and various other tumor
cells to multiple anticancer drugs (85, 91, 92). Inhibition of
MEK-ERK1/2 activity also decreases isothiocyanates- and
20 -hydroxycinnamaldehyde-induced apoptosis and cell
growth (93, 94).
How ERK1/2 activation promotes apoptosis is not well
understood. In radiation-induced apoptosis, PKC d enhances
the cytotoxic eect by allowing cells to escape from radiation-
induced arrest in the G2-M phases (69). However, this eect is
reduced when radiation-induced ERK1/2 activity is inhibited
by a MEK inhibitor (95). Treatment of human leukemia U937
cells with EGF activates ERK1/2, which in turn phosphor-
ylates Ser147 of tis21 and induces the interaction between tis21
and Pin-1, mitochondrial depolarization, G2-M arrest, and
cell apoptosis (96). Inhibition of ERK1/2 activity by MEK
inhibitors or a dominant-negative mutant of MEK1 reduces
cisplatin-induced increases in Bax expression, mitochondrial
membrane depolarization, mitochondrial cytochrome c re-
lease, caspase-3 activation, and cell apoptosis (97 99).
Doxorubicin activates ERK2, which in turn associates with
and phosphorylates p53 at Thr55, thereby increasing p53
transcriptional activity (100). Overexpression of p53T55A
suppresses the activity of endogenous p53 in MCF7 breast
cancer cells, enhances expression level of Bcl-2, and signi-
cantly increases drug resistance toward doxorubicin (92).
Cisplatin-induced phosphorylation of p53 at serine 15,
increase of p53 protein half-life, and accumulation of p53
downstream gene expression such as p21WAF-1 and MDM2 in
A2780 ovarian carcinoma cells are blocked by inhibition of
ERK1/2 (88). Nevertheless, ERK-independent regulation of
p53 was also reported. ERK activation increases cisplatin-
induced cell death in osteosarcoma and neuroblastoma cell
lines (91) and mediates cell cycle arrest and apoptosis in
response to etoposide, adriamycin, and ionizing irradiation
(85) in a p53-independent manner. Thus, upregulation of p53
activity by ERK activation during apoptosis appears to be
dependent on types of cell lines and stimuli, and the
mechanism by which ERK1/2 activation promotes apoptosis
warrants further investigation.
CONCLUSIONS
The ERK1/2 cascade is a central signaling pathway
responsive to a large number of extracellular stimuli. ERK1/
2 can be activated transiently or persistently by dierent
MAP3Ks in conjunction with involvement of various scaold-
ing proteins and phosphatases. Activated ERK1/2 executes its
function through a large number of downstream molecules.
The targeted selection of ERK1/2 downstream substrates
depends upon the cell type, nature of the stimuli that specify
627
the combination of three tiers of kinases, cellular compart-
ments in which ERK1/2 is localized, and interaction between
ERK1/2 and substrates. The specicity of activation or
inhibition of downstream eectors determines the consequence
of ERK1/2 activation on cell survival, which is anti-apoptotic
but in some cases pro-apoptotic. Further elucidation of how
ERK1/2 executes its function through downstream factors will
help us understand completely ERK1/2 function in cell
survival and apoptosis.
ACKNOWLEDGMENTS
We thank Oliver Bogler, Pamela Woodring, David Giegel,
John de Groot and Theresa Willis for their critical reading of
the manuscript and Dexing Fang and Yanhua Zheng for
preparation of the gures and table.
This work was supported by National Cancer Institute
grant 1R01CA109035-01A1 (Z.L.), the Pediatric Brain Tumor
Foundation (Z.L.), the Charlotte Geyer Foundation (Z.L.),
and an institutional research grant from The University of
Texas M. D. Anderson Cancer Center (Z.L.).
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