Mitogen-activated protein kinases: new signaling pathways functioning in cellular responses to environmental stress
1 Department of Surgery, Surgical Research Laboratory, San Francisco General
Hospital and University of California, San Francisco, San Francisco,
California 94110, USA
2 Institute of Biochemistry, College of Natural Sciences, Carleton
University, Ottawa, Ontario, Canada K1S 5B6
* Author for correspondence (e-mail: kenneth_storey{at}carleton.ca)
Accepted 10 January 2003
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Summary |
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Key words: extracellular signal-regulated protein kinase, c-Jun-N-terminal kinase, p38 kinase, signal transduction, freeze tolerance, anoxia tolerance, osmoregulation
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Introduction |
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The MAPK superfamily |
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ERK module
The ERK module responds primarily to growth factors and mitogens and
stimulates transcriptional responses in the nucleus. ERK1 and ERK2, the
best-studied of the group, are activated by MAPK/ERK kinase (MEK) 1 and MEK2,
which phosphorylate at the Thr-Glu-Tyr motif
(Cobb and Goldsmith, 1995).
The MEKs, in turn, are activated by c-Raf, the MAPKKK of this signaling
pathway, that is in turn regulated by growth factor receptors and tyrosine
kinases activating through Ras (Moodie and
Wolfman, 1994
). Upon translocation to the nucleus, ERKs are
responsible for the phosphorylation of multiple substrates, depending on the
initial stimulus. These include activators of transcription including p90 RSK
S6 kinase (Frodin and Gammeltoft,
1999
), MAPK-activated protein kinase-1, MAPKAP-K1, phospholipase
A2 and MSK, as well as transcription factors (Elk-1, Ets 1, Sap1a,
m-Myc), STAT (signal transducers and activators of transcription) proteins
such as Stat3, adapter proteins such as Sos, growth factor receptors such as
epidermal growth factor (EGF), and the estrogen receptors
(Denhardt, 1996
). Generally,
activation of an ERK signaling pathway has a role in mediating cell division,
migration and survival. ERK1/2 and MEK1/2 are also strongly activated during
muscle exercise and may provide the link between exercise and adaptive changes
in skeletal muscle composition (Widegren
et al., 2000
).
JNK module
There are three types of JNKs. JNK1 and JNK2, gene products of alternative
splicing, are widely expressed in many tissues, whereas JNK3 is brain-specific
(Davis, 2000). JNKs respond to
a variety of stress signals including heat shock, osmotic stress,
pro-inflammatory cytokines, ischemia and UV exposure
(Pombo et al., 1994
;
Hoeflich and Woodgett, 2001
;
Irving and Bamford, 2002
). The
JNKs are activated by dual phosphorylation at the Thr-Pro-Tyr motif by JNKK1
and JNKK2, also known as MAPK kinase 4 (MKK4) and MKK7
(Tournier et al., 1999
).
Upstream of the MKKs are their MAPKKKs, which include MEKKs 1-4, ASK, and a
member of the mixed-lineage kinases (MLKs;
Hirai et al., 1996
). In turn,
these are activated by GTP-binding proteins of the Rho family (Racs, Rhos, the
Cdc42s) (Teramoto et al.,
1996
). The MLKs can also be activated by a germinal center kinase
(GCK) family member, and thus activation of JNK can occur independently of the
GTPases (Yuasa et al., 1998
).
JNKs are active as dimers to translocate across the nuclear membrane. JNKs
were originally identified as the major kinases responsible for the
phosphorylation of c-Jun, leading to increased activity of the AP-1 (activator
protein-1) transcription factor (summarized in
Shaulian and Karin, 2002
);
other nuclear transcription factors are also now known to be targets including
ATF-2, Elk-1, Myc, Smad3, tumor suppressor p53, NFAT4, DPC4 and MADD, a cell
death domain protein (Atfi et al.,
1997
; Zhang et al.,
1998
; Hoeflich and Woodgett,
2001
). This selective focus on transcription factors contrasts
with the actions of the ERK and p38 MAPKs, which phosphorylate targets both
inside and outside the nucleus (Hoeflich
and Woodgett, 2001
). JNK-regulated transcription factors help to
regulate gene expression in response to a variety of cellular stimuli,
including stress events, growth factors and cytokines
(Whitmarsh et al., 1995
).
Activation of the JNK signaling cascade generally results in apoptosis,
although it has also been shown to promote cell survival under certain
conditions (e.g. in cardiac myocytes after oxidative stress;
Dougherty et al., 2002
) and
has important roles in determining cell fate during metazoan development
(Lisovsky et al., 2002
;
Moreno et al., 2002
) as well
as involvement in tumorigenesis and inflammation.
p38 module
Enzymes in the p38 MAPK module are subject to dual phosphorylation at the
Thr-Gly-Tyr motif and are generally activated by environmental stresses,
including heat, osmotic and oxidative stresses, ionizing radiation and
ischemia-induced vasoactive stresses, as well as inflammatory cytokines and
tumor necrosis factor (TNF) receptor signaling
(New and Han, 1998). The
upstream kinases acting on p38 include MKKs 3 and 6. These upstream kinases
have preferential effects on different p38 isoforms
(Chan-Hui and Weaver, 1998
),
which are in turn activated by MEKKs, MLKs and ASK1
(Fig. 1). GTPases are
responsible for the transmission of stress stimuli to the MAPKKKs of this
pathway, including the Racs, the Rhos and the Cdc42s. The five p38 isoforms
defined to date (p38
, p38ß, p38
, p38
and p38-2)
vary, based on their substrate specificity. The
and ß isoforms of
p38 are responsible for the activation of heat shock proteins (hsps) 25, 27
and the MAPK-activated protein (MAPKAP)-2. The
and
isoforms of
p38 activate ATF2, and p38-2 phosphorylates ATF2 and Sap-1a
(Stein et al., 1997
). Other
transcription factors affected by the p38 family include Stat1, Max/Myc
complexes, MEF-2A/C, Elk-1 and CREB through the activation of MSK1. Therefore,
the p38 subfamily is also involved in affecting cell motility, transcription
and chromatin remodeling (Kyriakis and
Avruch, 2001
). Other substrates of the p38 signaling pathway
include ATF2 and CHOP for regulation of gene expression, as well as MAPKAPK3,
MAPKAPK5 and Mnk1 (Beyaert et al.,
1996
; Huot et al.,
1997
; Zhu and Lobie,
2000
).
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MAPKS and comparative biochemistry |
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Studies in our laboratory have analyzed multiple facets of biochemical
adaptation by anoxia-tolerant and freeze-tolerant animals (for recent reviews,
see Storey, 1996,
1999
;
Storey and Storey, 2001
) and
recently we began to look at the role that MAPKs play in these processes. To
date, much of the research on MAPKs in vertebrates has centered on mammals,
with frequent use of isolated cell systems where stressors and effectors can
be applied in vitro. Our aim in initial studies was to find out how
MAPKs responded to stresses imposed upon the whole animal in vivo.
Data gathered from these initial studies have identified stress-specific,
organ-specific and time-dependent responses by one, two or all three of the
MAPK modules, and clearly show that MAPK signal transduction cascades have
roles to play in metabolic adaptation by anoxiaor freezing-tolerant species.
Initial work assessed three systems: (1) responses to whole animal freezing at
2.5°C by the freeze-tolerant wood frog Rana sylvatica, (2)
responses to anoxic submergence at 7°C by anoxia-tolerant adult red-eared
slider turtles Trachemys scripta elegans, and (3) responses to both
anoxia at 5°C and freezing at 2.5°C by hatchling sliders that
are tolerant of both stresses (Greenway and Storey,
1999
,
2000a
,b
).
Our initial data showed one common result: ERKs have little or no
involvement in the responses to freezing or anoxia in frogs and turtles. The
only substantial response by ERKs was an increase in the content of active,
phosphorylated ERK2 in frog brain as an early response to freezing
(Greenway and Storey, 1999).
Since the ERK pathway is believed to transduce signals primarily from growth
factors and mitogens, this result is not surprising.
JNKs and p38 responded to freeze/thaw and JNKs responded to anoxia. JNK
activities were not affected in wood frog organs over a 12 h freezing exposure
but activities were reduced by 4050% in turtle liver and heart over a 4
h freeze (Greenway and Storey,
1999,
2000a
). By contrast, JNK
appears to play a role in metabolic recovery after thawing in frog organs; JNK
activity increased strongly after 90 min thawing in liver and kidney (rising
approx. fiveand fourfold, respectively) and after a longer time (4 h) in
heart. JNK activity also rose during survivable anoxia exposure in tissues of
both adult and hatchling turtles (Fig.
2A); in both cases, JNK rose to a peak after 5 h of anoxic
submergence but fell with longer exposure (Greenway and Storey,
1999
,
2000b
). This suggests a role
for JNK activation in the hypoxia transition period during the early hours of
submergence with JNK suppressed again when metabolic arrest responses are
fully developed to support long term anoxia survival.
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The p38 MAPK was activated by freezing in wood frogs
(Greenway and Storey, 2000a).
The amount of active, phosphorylated p38 increased strongly in liver and
kidney within 20 min after freezing began but this was reversed by 60 min
(Fig. 2B). This suggests that
p38 may be involved in mediating one or more of the rapid, initial metabolic
responses to freezing such as the upregulation of multiple genes
(Storey, 1999
;
Storey and Storey, 2001
). The
activity of p38 in heart followed a different time course, with phospho-p38
(the active form) rising only after 1 h of freezing and continuing to 12 h.
Organ-specific activation of p38 also occurred during thawing but the
phospho-p38 content of wood frog liver and kidney did not respond to two
component stresses of freezing (anoxia, dehydration) when each stress was
applied individually (Greenway and Storey,
2000a
). This suggests that p38 may stimulate metabolic responses
that are unique to freeze/thaw. The amount of phospho-p38 was also unchanged
in turtle organs over the course of a 20 h anoxia exposure
(Greenway and Storey,
2000b
).
The lack of p38 responses to anoxia by anoxiaor freeze-tolerant animals
contrasts with studies of anoxia/hypoxia-sensitive species.
Ischemiareperfusion damage in mammalian heart is linked with activation
of p38, and attenuation of the p38 response to sustained ischemia by means of
short preconditioning exposures (that transiently activate p38) resulted in
improved recovery of function during reperfusion
(Marais et al., 2001). In
mammalian kidney, ischemia induced the activation of both JNK and p38 and
phosphorylation of MKK 7, MKK4 and MKK 3/6; preconditioning attenuated these
responses and correlated with improved survival
(Park et al., 2001
). Hence,
although much research remains to be done, it is interesting to speculate that
some of the significant differences in metabolic responses to anoxia between
anoxia-tolerant and intolerant species are mediated via JNK and p38
signal transduction pathways.
MAPK pathways also responded to anoxia, hyperosmotic and thermal stresses
as well as mechanical overload in the perfused heart of the frog Rana
ridibunda (Aggeli et al.,
2001a,b
,
2002
). Hyperosmotic stresses
(via perfusion with high sorbitol, NaCl or KCl) stimulated a rapid
phosphorylation of p38 that was readily reversible, whereas hypotonicity did
not affect the enzyme; both high and low temperatures elevated phospho-p38
content (Aggeli et al., 2002
).
High perfusion pressure also stimulated a rapid (30 s) phosphorylation of p38
and a prolonged (up to 30 min) phosphorylation of JNK
(Aggeli et al., 2001a
). JNKs
were also activated by anoxia/reoxygenation
(Aggeli et al., 2001b
). It is
interesting that both of these MAPKs also respond to freeze/thaw in wood frog
heart and, notably, freezing and thawing cause major changes in peripheral
resistance and blood viscosity that affect heart work load.
The responses of the p38 MAPK (or its yeast/fungal homologue HOG1) to
osmotic and volume stresses have been documented in many organisms including
yeasts, fungi (Zhang et al.,
2002), plants (Munnik and
Meijer, 2001
) and mammalian kidney
(Chen and Gardner, 2002
), liver
(vom Dahl et al., 2001
), and
brain astrocytes (Xu et al.,
2001
). New studies by Kultz and Avila
(2001
) probed the role of
MAPKs in osmosensory signaling pathways in gills of the fish Fundulus
heteroclitus. Total ERK and JNK protein contents were not affected by
either hyper-or hyposmotic stress, but p38 content rose significantly during
hyperosmotic stress. However, the activity (amount of phosphoenzyme) of all
three MAPKs increased significantly during hyposmotic stress and, oppositely,
decreased under hyperosmotic stress. These data demonstrate a key role for
MAPKs in salinity adaptation and will undoubtedly fuel a `renaissance' of
interest in the molecular mechanisms of osmoregulation in euryhaline
organisms.
The above studies clearly indicate that MAPKs have key roles to play in
animal responses to a wide variety of environmental stresses. Among the
obvious next steps in these studies is to identify both the downstream targets
of MAPK action and upstream signals that initiate MAPK activation in response
to stress. MAPKs have major roles as regulators of gene expression and, hence,
a major focus for MAPK studies in comparative systems will be on
stress-induced gene expression. In this search, new cDNA array gene screening
technology will prove to be critical. Indeed, its value is exemplified in a
recent paper by Nahm et al.
(2002), where cDNA array
screening technology was used to identify 12 genes that were upregulated by
hypertonicity in an inner medullary collecting duct cell line from mammalian
kidney. Cell lines were then treated with inhibitors of various protein
kinases and from this it was shown that MAPKs were commonly involved in the
induction of hypertonicity responsive genes. This study emphasizes not only
the key role of MAPKs in mediating responses to osmotic stresses in cells but
also the tremendous potential of cDNA array screening for gaining a `global'
view of cellular responses to stress. Having identified the genes that are
MAPK responsive, future studies can then go on trace the full regulatory
cascade involved and characterize the adaptive function of the protein
products of these upregulated genes.
A similar approach will undoubtedly prove effective in many comparative
systems, particularly those that are amenable to in vitro study and
treatment with externally added modifiers of MAPK activity (e.g. fish gill,
frog or turtle hepatocytes, mollusc mantle). Indeed, we are finding cDNA array
screening to be of great value in comparative systems. For example, a recent
analysis of anoxia-induced gene expression in hepatopancreas of the marine
snail, Littorina littorea using human 19 000 gene glass microarrays
showed low cross-reactivity (only 18.35%), but nonetheless still allowed us to
analyze the effects of anoxia on nearly 3500 genes, over 300 of which appeared
to be upregulated in anoxia. These represented a wide selection of protein
phosphatases and kinases, MAPK-interacting factors, translation factors,
antioxidant enzymes and nuclear receptors
(Larade and Storey, 2002). Few
of these proteins have ever been implicated before in anoxia adaptation and
this opens the door to expanded studies of the genes/proteins involved in
anoxia tolerance and the signal transduction systems that regulate them.
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Control of MAPKs |
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Regulation by MAPKKK specificity
One way to achieve specificity of a pathway is via the type of
MAPKKK activated by a signal. For example, specificity in the ERK signaling
cascade depends on which isoform of Raf (the MAPKKK of the pathway) is
activated. Mouse knock-out studies have shown that each of the three isoforms
(Raf-1, BRaf, A-Raf) have distinct roles. Raf-1 has a general and crucial role
in the development of all tissues, whereas A-Raf defects result in
neurological and intestinal problems and B-Raf defects die because endothelial
cells fail to mature, leading to vascular haemorrhaging
(Hagemann and Rapp, 1999).
Regulation by scaffolding proteins
ERK activation is a cascade event that results in the formation of large,
multimeric signaling complexes. For example, Raf interacts with Ras-GTP, MEKs
then bind to Raf, and ERKs bind to the N terminus of MEK. Recently discovered
is the MP1 protein (MEK partner 1), a scaffolding molecule that appears to
bind to a subgroup of proteins within a MAPK module, and therefore it favors
the specific activation of certain components within the module
(Schaeffer et al., 1998). MP1
is believed to play a significant role in specificity within the MAPK module
for it interacts only with ERK1 and MEK1, and not with ERK2 and MEK2, and
hence favors the activation of ERK1. MP1 also augments Raf activation of MEK.
Other potential scaffolding proteins in the ERK module are also being
investigated. Thus, it is believed that ERK signaling is regulated dynamically
by the binding of scaffolding proteins such as MP1, which affect
proteinprotein interactions, and therefore sway the status of stability
within a module and affect the outcome of the stimulus.
The JNK cascade also has a scaffolding protein. JIP1 binds specifically to
JNK1, as well as to MKK7, and the MKK7 activators MLK3 and DLK (dual leucine
zipper-bearing kinase) (Whitmarsh et al.,
1998). JIP1 is highly specific to binding and activating the JNK
cascade, and is probably involved in organizing this signaling module in order
to permit upstream regulation. The JNK signaling pathway is also regulated by
adapter proteins that couple to the TNF receptors, the family of receptors
that are probably the most important activators of this pathway. The
TNFR-associated factors (TRAFs) couple to upstream activators of the JNK
signaling pathway as well as to the stress-activated kinase itself
(Bradley and Pober, 2001
). The
six TRAFs known to date are each activated in response to various TNFR
signaling ligands.
Regulation by cellular location
ERK activity is also regulated by subcellular location. For example, during
mitosis, studies have shown that activated ERKs associate with CENP-E, a
centromeric protein (Zecevic et al.,
1998), at the kinetochores, and on the mitotic apparatus
(Willard and Crouch, 2001
),
implicating their importance during M phase. JNK colocalizes in certain cells
with its MAPKKK, MLK2, along microtubules
(Nagata et al., 1998
). The
subcellular location of downstream substrates of JNK is also affected by JNK
phosphorylation, such as the transcription factor NFAT4 (nuclear factor of
activated T cells), which is involved in differentiation and cytokine gene
expression (Chow et al.,
1997
). Phosphorylation by JNK prohibits this transcription factor
from entering the nucleus and thereby inhibits NFAT4 signaling. The regulation
of the p38 signaling pathway by scaffolding and adapter proteins is not well
understood but activated p38 can regulate the distribution of some of its
substrates. For example, the phosphorylation of both p38 and its substrate,
MAPKAP kinase 2, causes both proteins to be excluded from the nucleus
(Ben-Levy et al., 1998
). In
addition, NFATc4, a substrate of p38 but not of JNK, must be dephosphorylated
in order to enter the nucleus to activate transcription
(Yang et al., 2002
).
Regulation via stimulus intensity
For specific biological responses, the timing and duration of the stimulus
also has a direct impact on the type of response that cells make to a signal
as well as the cell type affected. Thus, sustained or transient signals
through ERK, for example, will determine whether a cell's response is growth
or differentiation (Kao et al.,
2001). In turn, the duration of the signal, whether it is
transient or prolonged, could rely on feedback pathways through
phosphorylation, although the relevance of these feedback mechanisms has yet
to be deciphered.
Phosphatases
Since MAPKs are activated by phosphorylation, the protein phosphatases that
dephosphorylate MAPKs are a key element in their control. Three families of
protein phosphatases are involved: Ser/Thr phosphatases, Tyr phosphatases and
dual specificity Ser/Thr/Tyr phosphatases
(Tamura et al., 2002). Some
have received considerable attention. MAPK phosphatase-1 (MKP-1) and MKP-2 are
not specific and dephosphorylate the ERKs, JNKs and p38
(Chu et al., 1996
), whereas
MKP-3 appears to be specific to ERK1 and ERK2 only and JNKs and p38 are
inactivated by the phosphatase M3/6 (Muda
et al., 1996
). The activities of MKPs are also defined by their
subcellular location. MKP-3 is known to be cytoplasmic, whereas MKP-1 is only
found in the nucleus. In addition serine/threonine protein phosphatases 1 and
2A have been implicated in MAPK signaling cascades, although whether the
dephosphorylation of their substrates has any pertinent role in vivo
has yet to be determined.
Signaling crosstalk
Although the three MAPK modules run in parallel
(Fig. 1), there is a
considerable degree of cross-talk between them, which creates multiple
opportunities for modulating or fine-tuning responses to different signals.
Specificity of the MAPK signaling pathways is greatest at the level of
specific MKK activation of individual MAPKs, where there is the least amount
of cross-talk. Although some substrates are activated very specifically by
only one of the three pathways, there is often considerable cross-talk at the
MAPK substrate level (e.g. Elk-1 is phosphorylated by all three MAPK signaling
pathways; Yordy and Muise-Helmericks,
2000). The MAPKKKs are also involved in cross-talk, although much
remains to be elucidated at this level.
Fig. 3 outlines various known
cross-talk interactions among the MAPK pathways. Obviously, there is potential
for a considerable level of communication between these MAPK modules, the type
and amount of which can vary widely depending upon factors, including the
length, intensity and timing of signal, type of cell, and cell-specific
receptor distribution at the plasma membrane.
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MAPK cascades can also influence other signaling pathways and vice
versa; there are several known examples of MAPK influences on outside
signaling pathways. For example, ERKs can activate the JAK-STAT pathways
(Marshall, 1995). MAPKs can
also converge on the same substrates. Thus, both ERK and p38 activate MNK1
(Fukunaga and Hunter, 1997
),
the MAPK signaling-integrating kinase 1, which is responsible for the
activation of the eukaryotic translation initiation factor 4E, as well as
MSK1. ERK, p38 and JNK all also phosphorylate the transcription activators
MAPKAP kinase 3 and Elk-1, whereas p38 and JNK both phosphorylate ATF2, and
ERK and JNK both activate c-Jun.
MAPK signaling cascades are influenced by other signaling pathways,
including those linked with cAMP and calcium. The MEKs that activate ERKs can
be activated by specific Raf isoforms based on the type of cell stimulated and
the level of cAMP generated. Calcium signaling also affects ERK modules; it
has been shown in cardiomyocytes and neurons that calcium influx results in
MEF2 activation, a transcription factor that is a substrate for the
calcium/calmodulin-dependent protein kinase IV
(Mao et al., 1999;
Lu et al., 2000
). The
activation of MEF2 correlates with the activation of p38, which is responsible
for the phosphorylation of MEF2 on its activation site.
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Conclusions and perspectives |
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Acknowledgments |
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References |
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