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Introduction
Cells have to respond to environment stimuli properly to survive. These stimuli include physical stimulation such as heat,
pH variation, radiation, redox, osmolarity, and chemical stimulation such as growth factors, cytokines, hormones, alterations
in nutrient conditions, as well as other environment
stresses[1]. These stimuli control many aspects of complex cellular
processes, including the regulation of gene expression, cell survival, growth, differentiation and death. In these processes,
many signal transduction pathways cooperate to relay, amplify, and integrate a diverse range of extracellular stimuli. The
mitogen-activated protein kinase (MAPK) signaling pathway is one of the major signaling systems that transduce
extracellular signals into cells[1,2] (Figure 1).
MAPK pathways are conserved in fungi, plants, and mammals. MAPK cascades contain at least 3 protein kinases in
series. They are MAPK kinase kinases (MAPKKK, also known as MEKK), MAPK kinases (MAPKK, also known as MEK
and MAPK). MAPKKK phosphorylate and activate the downstream MAPKK, which in turn phosphorylate and activate
MAPK (Figure 1). These kinases are activated by dual
phosphorylation[1_3]. As there are many different extracellular signals
in the cellular contexts, MAPKKK show high divergence in structure and gene number compared with MAPKK and MAPK.
Typically, MAPKKK are regulated through receptor activation, membrane recruitment of adaptor molecules, activation of
small GTP-binding proteins, and phosphorylation. The activation of the cascades may also require additional kinases
upstream of this 3-tier kinase, as well as scaffold proteins that are able to manage the complexity and specificity of the
pathway. The scaffold proteins can bind, organize, and facilitate specific interactions among the components so that specific
stimuli can produce specific MAPK signaling responses (Figure
2)[2,4]. Because of the implication of MAPK in developmental
processes and the survival/death responses of cells to their environment, the MAPK pathway has become the focus of
attention in recent years[5].
In mammals, there are 3 subfamilies of MAPK that have
been identified up to now: c-Jun N-terminal protein kinases
(JNK)/stress-activated protein kinases (SAPK), p38 MAPK,
and ERK (Figure 1)[2,6]. Following the same signaling
arrangement, each individual MAPK pathway responds to
specific stimuli and then regulates their specific substrates.
This review will focus on the JNK MAPK pathway and its
involvement in a variety of diseases.
JNK MAPK pathway
The mammalian JNK were initially described as SAPK
because they are activated in response to a variety of
environmental stresses[7,8]. The JNK pathway is also recognized
to respond to cytokines (eg, TNF and interleukin-1) and
growth factors[9].
JNK is a multifunctional kinase involved in many
physiological and pathological processes. The JNK pathway plays
a major role in apoptosis in a variety of death paradigms. For
example, the JNK pathway is required for neuronal cell death
induced by many apoptotic stimuli, including nerve growth
factor (NGF) deprivation, trophic support withdrawal, DNA
damage, oxidative stress, α-amyloid exposure, low potassium,
excitotoxic stress, 6-OHDA, UV irradiation, and tumor
necrosis factor[10_19].
The JNK pathway cascade involved in neuronal cell
death has been widely studied. It mainly contains activated
Rac1/Cdc42, mixed-lineage kinases (MLK) and/or ASK1,
MKK 4 and MKK7, and JNK in
series[1,10,15_18,20]. In addition, other components are involved in the activation of the JNK
pathway[16,18,19]. Furthermore, plenty of SH3 (POSH) and JNK
interacting proteins (JIP) have been shown to act as a
scaffold protein to form a multiprotein complex with other JNK
apoptotic cascade elements[15,21,22].
In mammals, there are 3 JNK genes: Jnk1,
Jnk2, and Jnk3 on 3 different chromosomes, and each
mammalian JNK gene has alternative splicing forms so there are at least 10
different JNK proteins of 46_55 kDa
identified[23]. JNK1 and JNK2 are ubiquitously expressed, but the expression of JNK3 is
mainly restricted to central nervous system (CNS) neurons
(high level), cardiac smooth muscle, and testis (low
levels)[10]. There is a different substrate affinity among these
10 isoforms[23]; therefore, different JNK isoforms could play
specific roles in multicellular organisms, and there is also
complementation between the JNK genes.
As to the substrates of JNK, initially studies found that
JNK can interact with and phosphorylate the N-terminal
transactivation domain of c-Jun and thereby enhance its
ability to transactivate related gene expression, so it is called
JNK[24]. However, ongoing studies show JNK can
phosphorylate a variety of substrates, including additional
transcription factors and even some non-nuclear proteins. In
addition to c-Jun, JNK can phosphorylate transcription factors
such as JunB, JunD, c-Fos, and ATF. These transcription
factors, together with c-Jun, constitute activator protein-1
transcription factors, which can regulate the expression of
several stress-responsive genes[25]. There are other
transcription factors such as ElK1, NFAT, and p53 that can also
be phosphorylated by JNK[28]. JNK mediates apoptosis not
only through its effects on gene transcription, but also
through a transcriptional-independent
mechanism[29]. Several studies have demonstrated that JNK is able to
phosphorylate both pro- and anti-apoptotic proteins and regulate
their activity. For example, JNK can phosphorylate Bcl-2
and Bcl-xL and diminish their anti-apoptotic
activity[30_32]. JNK can also phosphorylate the pro-apoptotic protein Bim
and Bmf to promote their pro-apoptotic
effects[33,34].
Involvement of the JNK pathway in diseases
The JNK pathway is involved in many physiological
processes such as embryonic morphogenesis and
naturally-occurring programmed cell death. The specific roles that
JNK plays depend on the cellular
context[10]. Under pathological conditions, the unusual activated JNK pathway can
cause pathological cell death and different diseases.
JNK pathway and neurological disorders Mounting
evidence suggests that the JNK pathway plays critical roles in
the pathogenesis of many neurological disorders, including
ischemic stroke, Parkinson's disease (PD), polyglutamine
diseases, amyotrophic lateral sclerosis, auditory hair cell
degeneration in addition to different tauopathies, which
include Alzheimer's disease (AD), Pick's disease, progressive
supranuclear palsy, corticobasal degeneration, argyrophilic
grain disease, familial frontotemporal dementia, and
parkinsonism.
Hyperphosphorylation and the accumulation of tau in
neurons (and glial cells) is one of the main pathological
hallmarks in AD. Increased levels of activated JNK have been
found in brain homogenates in all the tauopathies. Strong
active JNK immunoreactivity has been observed to be
restricted to neurons and glial cells containing
hyperphos-phorylated tau, as well as in dystrophic neurites of senile
plaques in AD[35]. The accumulation of amyloid beta peptide
(Abeta) is believed to be an early and critical event leading
to synapse and neuronal cell loss in AD. Abeta itself is toxic
to neurons in vitro, and the expression of Abeta
in vivo causes the loss of synapses and neurons in the brain in
animal models[36]. Interestingly, the increased expression
level of activated forms of JNK and p38 and
hyperphos-phorylated tau containing neurites has been observed in
mice transgenic of human amyloid precursor protein-695 with
the Swedish familial AD mutations (Tg2576) and a P264L
familial AD mutation introduced by targeting the
presenilin-1 gene[36]. In the Tg2576 model, JNK activity is associated
with the 2 hallmarks of AD: the amyloid deposit and the
hyper-phosphorylated Tau protein[36].
Reactive oxygen species (ROS) has been considered to
be the major cause of Abeta toxicity and it is believed that
the Abeta-triggered generation of ROS leads to the
activation of the JNK pathway, which in turn phosphorylates tau
in neurites surrounding amyloid
deposits[35,37]. Corresponding evidence has been reported from the autopsies of AD
patients who participated in the amyloid-beta immunization
trial and died from the immunization-induced encephalitis.
The activation of JNK was reduced together with decreased
tau hyperphosphorylation of aberrant neurites in
association with decreased amyloid plaques in both Tg2576 mice
and human brains[35]. Thus, pharmacological inhibitors of
JNK may also offer neuroprotection for AD.
JNK signaling has been implicated in the animal model of
MPTP-induced degeneration of neurons in the substantia
nigra. Following MPTP injection, the obvious activation of
JNK, the downstream substrate of JNK, c-Jun, and the
upstream kinase MKK4 have been detected in the
substantia nigra, correlating with the death of dopaminergic
neu-rons[12,38]. A peptide JNK inhibitor interferes with the
interaction between JNK and JIP, and inhibits MPTP-induced
JNK activation and cell death in the substantia
nigra[39]. Gene targeting studies have shown that JNK2 and JNK3 play a
vital role in MPTP-induced neuronal death in the substantia
nigra. These results, along with the neuroprotective effects
by the JNK-pathway inhibitor CEP-1347 in animal MPTP
models, have propelled JNK signaling to be a promising
target for the pharmacological treatment of the
PD[40].
For ischemic stroke, increased activity of JNK was found
to co-localize with TUNEL-labeling in the peripheral area of
focal ischemia animal models[41]. JNK3 knockout mice are
remarkably resistant to kainic acid-induced
excitotoxicity[10]. Subsequent studies further showed that JNK3-deficient mice
had increased resistance to a global ischemia-hypoxia model
of stroke[42]. JNK3 deficiency renders reduced Bim and Fas
expression after stroke, and JNK3-null hippocampal neurons
have less cytochrome c release following oxygen-glucose
deprivation[42]. Furthermore, mice lacking the JNK signaling
scaffold protein JIP1 have increased resistance to the
gluta-mate excitotoxicity[43] and reduced infarct size in a focal
ischemia model of stroke[44]. Knockdown of another
scaffold protein POSH is neuroprotective following cerebral
ischemia in the rat hippocampus[45]. Taken together, these
studies indicate that the JNK pathway may play an
important role in ischemic cell death. It offers an opportunity to
develop or apply inhibitors of JNK to treat neuronal cell
death incurred by ischemia.
JNK pathway and other diseases It has been recognized
that the JNK pathway serves as a major "on" switch of
programmed cell death in response to a variety of
stimuli[46]. In addition to the well-established roles of JNK in neurological
disorders, the JNK signaling pathway plays unexpected
pathological roles in other diseases, including type 2 diabetes,
cancer, stroke, heart disease, and inflammatory diseases.
Type 2 diabetes is the most prevalent and serious
metabolic disease hallmarked by pancreatic beta-cell
dysfunction and insulin resistance. Under diabetic conditions,
oxida-tive stress and endoplasmic reticulum stress are induced in
various tissues, leading to the activation of the JNK
pathway[47].
Recent studies have demonstrated that JNK plays a
central role in modulating insulin action
and the pathogenesis of obesity, fatty
liver disease, and type 2
diabetes[48]. JNK can directly
phosphorylate IRS-1 at several sites,
including Ser307[49]. There
is increased JNK-dependent
IRS-1 Ser phosphorylation in obesity that
leads to reduced insulin-stimulated IRS-1 Tyr
phosphorylation. In obese animals, knockout of the JNK-1 gene, or the expression of a
dominant-negative JNK isoform, results in the
reversal of obesity-induced IRS-1
Ser phosphorylation and substantial protection
against insulin resistance and defective insulin
receptor signaling[4,48], while the exogenous expression of
JNK in the adult liver results in severe
insulin resistance in mice[4]. JIP1 in knockout mice creates a phenotype very
similar to JNK-1 deficiency with reduced
JNK activity and
increased insulin sensitivity[50].
Meanwhile, a point mutation in JIP1 has been identified
in type 2 diabetes patients, providing
crucial genetic evidence for the role of JNK and
JIP1 in the pathogenesis of type 2 diabetes in
humans[51].
It is likely that JNK activity modulates islet
function and/or survival in different ways. First, JNK is involved in islet
cell inflammation and death mediated by
cytokines[52_54]. Second, JNK
activation might cause β-cell dysfunction and
defective insulin production, thereby contributing to the
development of frank
diabetes[55]. Third, administration of
SP600125, an inhibitor of JNK, improves glucose-stimulated
insulin production in isolated islets in the db/db model
of obesity and diabetes[56]. Therefore, JNK might integrate
defects in insulin secretion with peripheral
insulin resistance in type 2 diabetes through its actions
in pancreatic β-cells as well as peripheral sites
of insulin action.
Taken together, there is very strong evidence that
abnormal JNK activation is a critical event in the deterioration of
glucose homeostasis and suppression of JNK in diabetic
mice. Thus, the JNK pathway plays a central role in the
pathogenesis of type 2 diabetes and could be a potential
target for diabetes therapy.
Development of JNK pathway inhibitors
In light of the mounting evidence indicating the
involvement of JNK signaling in different diseases, it is not
surprising that JNK signaling has been of particular interest for
drug development.
The complete elimination of JNK genes either alone or in
combination has been the initial approach in understanding
JNK function. It is very helpful for finding out the specific
JNK target for diseases. For example, JNK3 is primarily
localized in CNS neurons. Studies from JNK3 knockout mice
indicate that JNK3 is an attractive target for
neurodegenera-tion therapy in which neuronal cell death should be
prevented[10]. In addition, JNK1 knockout can protect mice from
obesity-induced insulin resistance, so JNK1 provides a
target for the treatment of type 2
diabetes[48]. However, the "knockout" strategy can not be used in disease therapy
because the long-term and complete loss of JNK pathway
would cause unwanted side-effects. So many alternative
approaches that can partly and temporally inhibit JNK
function have been developed in recent years. These approaches
include antisense techniques, RNAi techniques, and
chemical and peptide inhibitors. Some commonly used inhibitors
proved to be efficient for use both in
vitro and in vivo, indicating that the JNK pathway is suitable for therapeutic use.
There are mainly 3 types of inhibitors thoroughly
studied up to now. The first is the ATP-competitive inhibitor of
the JNK pathway such as CEP-1347 and SP600125. Most of
them are small organic compounds. Most drug discovery
programs have focused on designing this kind of inhibitors.
They occupy the ATP-binding site of the protein kinase,
which is structurally similar in all kinases, so the
phosphorylation of substrates is blocked. The ATP-competitive
inhibition can be specific, with each inhibitor recognizing the
specific ATP-binding site of each kinase. Up to now, at least 40
structurally-different small molecules have been
described[40]. However, there is also the disadvantage that the efficacy of
the ATP-competitive inhibitor can be reduced by the high
endogenous levels of ATP. This has been observed in
SP600125[57]. In addition to the ATP-binding site, other sites
on the kinase can also provide the target for inhibition, so
the second kind of inhibitor targets the substrate-binding
site. Based on this mechanism, many peptide inhibitors and
dominant-negative mutants against kinases have been
designed. The non-phosphorylatable substrate analogue
provides a good example of this kind. The third kind of
inhibitor targets the allosteric regulatory sites. Either
peptides or chemical non-peptides can be used if they can bind
to the regulatory sites and block the phosphorylation.
CEP-1347 CEP-1347, originally named KT7515 or 3,9
bis-[(ethylthio)methyl]-K252a, was initially identified as a
derivative of the natural compound K252a. The
indolocar-bazole K252a has both survival-promoting and neurotrophic
effects. Compared to K252a, CEP-1347 is more suitable for
therapeutic use because it retains the desirable properties of
K252a and minimizes the undesirable
effects[58]. For example, the natural compound K252a can inhibit the high affinity
nerve growth factor receptor Trk, protein kinase C, myosin
light chain kinase and cAMP-dependent protein
kinase[58], and calmodulin-activated
enzymes[59]. These inhibitory activities greatly limit its use as a neuronal therapeutic agent.
CEP-1347 has much lower inhibitory activity towards these
kinases.
Studies have shown that CEP-1347 can serve as a
neurotrophic molecule to maintain the trophic status of
neurons[60]. In addition, CEP-1347 can inhibit the activation of the JNK
pathway and thereby prevent neuronal death in both cell
culture and animal models. Pretreatment with CEP-1347
prevents β-amyloid-, NGF-withdrawal-, oxidative-stress-, and UV
irradiation-induced cell death in PC12 cells and rat
sympathetic neurons[11,13]. In the MPTP-model of PD, CEP-1347
can suppress JNK and MKK4 phosphorylation, as well as
MPTP-induced cyclooxygenase-2 expression, and protects
dopaminergic neurons[61,62]. In another model of
PD-intrastriatal injection of 6-hydroxydopamine in rats, the
CEP-1347 analogue CEP-11004 also diminishes the apoptotic death
of dopaminergic neurons[40]. Taken together, these studies
strongly implicate the protective functions of CEP-1347 in
animal models of PD.
In addition to PD models, the subcutaneously delivery
of CEP-1347 attenuates noise-induced hearing loss and
prevents neomycin and aminoglycoside-induced hair cell death
in guinea pigs[63,64]. CEP-1347 has also been applied to other
disease models that result from JNK activation such as
pancreatitis[65] and pulmonary
fibrosis[66].
As to the mechanism of inhibition, Maroney et
al found that the direct biochemical target of CEP-1347 was the MLK
family, the upstream kinase activator of JNK in the JNK
pathway[67]. By reducing the kinase activity of MLK, CEP-1347
selectively inactivates the JNK signaling pathway, but spares
the ERK and p38 MAPK pathways[60].
CEP-1347 has undergone phase II/III clinical trials for
neuroprotection in PD. It has been discontinued for lack of
clinical efficacy. Although disappointing, we have to keep
in mind that the dose of CEP-1347 used in the trials was not
high enough in order to avoid potential adverse effects. In
addition, although CEP-1347 can be effective in preventing
neuronal cell death, it may not improve the symptoms since
dopaminergic neurons were lost before treatment in PD
patients.
SP600125 The structure of SP600125
(anthrax[1,9-cd][yrazol-6{2H}-one]) is consistent with other known kinase
inhibitors. SP600125 is a reversible ATP-competitive
inhibitor of protein kinases. It targets all 3 JNK gene products
(JNK1, JNK2, and JNK3) by competing with the
ATP-binding site[57]. Since it inhibits JNK MAPK rather than upstream
components of the pathway, SP600125 is likely to produce
much more specificity of therapy effects than CEP-1347.
SP600125 has been shown to be effective in suppressing cell
death in the presence of different apoptotic
stimuli[18]. In the MPTP model of PD, SP600125 can partially restore dopamine
levels[68]. SP600125 has also been demonstrated in animal
models of asthma[69]. However, there are also some
disadvantages regarding this JNK inhibitor. First, it inhibits all
JNK isoforms. The JNK gene knockout studies mentioned
earlier have revealed isoform specific roles of JNK, so
compounds showing isoform selectivity would be preferred for
specific disease therapy. Second, at higher concentrations,
SP600125 has more effects than expected since MKK3 and
MKK6, and MKK4 and MKK7 are also
inhibited[57]. As MKK3 and MKK6 are upstream activators of the p38 MAP
kinase signaling pathway, the effects of SP600125 may not
be entirely due to the inhibition of JNK signaling especially
at higher concentrations. So we have to test the specificity
of SP600125 towards other kinases to evaluate its
therapeutic use. Third, because JNK is a terminal kinase in the
cascade, the inhibition of JNK may produce more general effects
compared to upstream kinase inhibition. Finally, SP600125 has
very poor water solubility. That is why its application in
neurological disorders and other disease models is limited
so far.
AS601245 AS601245 (1,3-benzothiazol-2-yl
(2-[[2-(3-pyridinyl)ethyl] amino]-4 pyrimidinyl) acetonitrile) has been
shown to inhibit the JNK signaling pathway similar to
SP600125. It inhibits JNK3 with IC50 of 70 nmol/L and
IC50 for JNK1 and JNK2 at 150 and 220 nmol/L,
respectively[70]. Thus, AS601245 appears to be a more selective inhibitor of JNK3 at
a low dose. AS601245 provides significant protection against
the delayed loss of hippocampal CA1 neurons in a gerbil
model of transient global ischemia. A significant
neuroprotec-tive effect of AS601245 was also observed in rats after focal
cerebral ischemia[70,71]. AS601245 has also been shown to
decrease cardiomyocyte apoptosis and infarct size after
myocardial ischemia and reperfusion in anaesthetized
rats[72]. The in vitro and in
vivo anti-inflammatory potential of AS601245 was investigated recently and found to
demonstrate efficacy in an experimental model of rheumatoid
arthritis[73]. It would be intriguing to investigate whether AS601245
has cytoprotective effects in animal models of
neurodegen-erative diseases.
Peptide inhibitors of the JNK pathway Peptide
inhibitors target the protein/peptide substrate binding sites or
regulatory sites of the protein kinases. This provides a more
specific inhibition mechanism than ATP-competitive inhibitor.
Many non-phosphorylatable substrate analogues have been
designed on the basis of substrate-competition.
As to the regulatory site inhibition, a non-substrate JIP
has been found in a 2-hybrid screen[21]. As mentioned earlier,
JIP act as scaffold proteins to form a multiprotein complex
with other JNK apoptotic cascade elements. However, JIP1
overexpression can block JNK activity in mammalian
cells[21] and cell death in several physiological
models[74]. This is probably because excess scaffold results from
overexpres-sion compared to the limited amounts of other JNK pathway
elements that disrupt the integrity of each complex.
The D-JNKI-1 peptide, a cell penetrating JNK inhibitor,
was constructed by linking the 20 amino acid segment of a
JNK-binding domain (JBD) from JIP1 to a 10 amino acid
HIV-TAT transporter sequence and by synthesizing a highly
protease resistant form of the JBD that doubles its intracellular
half-life[53]. It has been demonstrated to prevent loss of
hearing following either electrode insertion trauma or loss of both
hearing and hair cells following exposure to ototoxic levels
of neomycin[75]. D-JNKI also showed a remarkable
neuro-protective effect in both the transient and permanent
middle cerebral artery occlusion (MCAO) model of
stroke[76]. The protection correlated with the prevention of an increase in
c-Jun activation and c-Fos transcription. Importantly, DJNKI
reduces the infarct volume, even when administered at 6_12
h after transient MCAO. In view of its potency and long
therapeutic window, this protease-resistant peptide is a
promising neuroprotective agent for stroke.
Conclusions and perspectives
It has been recognized that the JNK pathway plays
important roles in many physiological and pathological
conditions. Therefore, JNK pathway components represent
potential therapeutic targets for the treatment of related
diseases, including neurodegenerative diseases, cancer,
diabetes, hearing loss, heart diseases, inflammatory diseases,
and autoimmune diseases. Several kinds of inhibitors have
been developed, targeting different levels of the JNK
signaling cascade and some of them, such as CEP-1347 and
SP600125, have been used in clinical trials. Although there
are still some problems limiting the use of these inhibitors
such as the substrate specificity, the crosstalk between the
JNK and other signaling pathway, and potential side effects,
including the possibility to induce tumor formation, we are
hopeful that effective drugs targeting the JNK pathway will
be developed for relevant diseases in the near future. To
reach this goal, further efforts are required to learn more
about the physiological roles of the JNK pathway
components while attention should be paid to develop more
specific inhibitors. In addition, long-term clinical studies are
needed to observe whether JNK pathway inhibitors would
lead to tumor formation and tumor metastasis in some
circumstances.
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