JNK3 as a Therapeutic Target for Neurodegenerative Diseases
c-Jun N-terminal kinases (JNKs) and in particular JNK3 the neuronal specific isoform, have been recognized as important enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the field of neurodegeneration for new therapeutic routes. However, in order to design new and more efficient therapeutical approaches careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling: they can modulate spatial and temporal activation of the JNK signaling and can thus provide the basis for the design of more specific inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons. Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the β-arrestin-JNK3 interaction is discussed.
Journal of Alzheimer’s Disease 24 (2011) 633–642
JNK3 as a Therapeutic Target for
Xanthi Antonioua, Mattia Falconib, Daniele Di Marinoband Tiziana Borselloa,∗
aIstituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
bDepartment of Biology and CIBB, Center of Biostatistics and Bioinformatics, University of Rome “Tor Vergata”,
Abstract. c-Jun N-terminal kinases (JNKs), in particular JNK3 the neuronal speciﬁc isoform, have been recognized as important
enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit
JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the ﬁeld of
neurodegeneration for new therapeutic routes. However, in order to design new and more efﬁcient therapeutical approaches
careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling:
they can modulate spatial and temporal activation of the JNK signaling and can thus provide the basis for the design of more
speciﬁc inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons.
Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the ␤-arrestin-JNK3 interaction
Keywords: JNK3, JIP1, ␤-arrestin-2, Alzheimer disease, signalling pathways, neuroprotection
The JNK family of protein kinases is one of the three
identiﬁed families of mitogen activated protein (MAP)
kinases. There are ten different JNK isoforms, which
are formed by alternate splicing of the three genes,
JNK1, JNK2, JNK3 . The isoforms differ somewhat
in their substrate speciﬁcity in vitro , although the
details of this are still unclear, but they have much
in common and can all phosphorylate members of the
AP-1 group of transcription factors as well as many dif-
ferent targets, both nuclear and cytoplasmic [1, 3–10]
summarized in Fig. 1.
Whereas JNK1 and JNK2 have a broad tissue dis-
tribution, JNK3 is mainly localized in neurons and to
a lesser extent in the heart and the testis .
∗Correspondence to: Tiziana Borsello, Neuronal Death and Neu-
roprotection Unit, Neuroscience Department, Istituto di Ricerche
Farmacologiche “Mario Negri”, Via La Masa 19, 20156 Milano,
Italy. Tel.: +39 02 39014469/39014592; Fax: +39 02 3546277;
JNK3 is a multifunctional enzyme important in
controlling brain functions under both normal and
The loss of JNK3 is not embryonic lethal. Nev-
ertheless JNK3 is implicated in processes such as
brain development , neurite formation and plastic-
ity (repair and regeneration) [13, 14] but also memory
and learning [15, 16].
Under pathological conditions, JNK3 has been
considered as a degenerative signal transducer. Sev-
eral evidences exist to support this idea. The JNK3
knockout (-/-) mice showed reduced apoptosis of
hippocampal neurons and reduced seizure induced
by kainic acid, a glutamate-receptor agonist .
JNK3-/- mice are also protected against ischemia.
Such studies have been performed both in neonatal
and adult rats, further reinforcing the contribution of
JNK3 in ischemia [18, 19]. In accordance with the
above, Kuan et al., reported that in vitro and follow-
ing oxygen-glucose deprivation hippocampal neurons
from JNK3-null mice are more resistant compared to
ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved
634 X. Antoniou et al. / JNK3 in Neurodegeneration
Fig. 1. Simpliﬁed diagram: JNK’s targets in the different neuronal compartments: nucleus, cytoplasm, mitochondria and synapse. JNK can
phosphorylate a range of substrates that are located in different parts of the neuron. In some cases, the consequences of JNK phosphorylation
could be ascribed to normal/positive effects while in others to pathological/negative/effects. In some cases the consequences have not yet been
deﬁned. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/JAD-2011-091567)
X. Antoniou et al. / JNK3 in Neurodegeneration 635
WT mice. The authors provided evidence for a critical
JNK3 role in both the apoptotic process and the release
of cytochrome c from mitochondria .
JNK3 activation is associated with chronic neu-
rodegenerative diseases. In MPTP, a mouse model
of Parkinson’s Disease, elimination of JNK3 (-/-)
prevented 50% of the triggered neurotoxicity; in this
model JNK2 also played a role [16, 20]. JNK3
activation is also described in Alzheimer’s disease
(AD). In fact JNK3 is highly expressed and acti-
vated in postmortem brains of individuals that suffered
from Alzheimer’s disease . Neurons derived (ex
vivo) from mice lacking JNK3 are resistant to A␤-
induced apoptosis when compared with neurons from
normal mice. Cleary et al.  demonstrated that
JNK3 is the major kinase for Beta-Amyloid Precur-
sor Protein (APP) phosphorylation at T668. This is an
important ﬁnding since APP is a conserved and ubiqui-
tous transmembrane glycoprotein strongly implicated
in the pathogenesis of AD and the toxic soluble
oligomers species (A␤1-42 oligomers) are produced
by the cleavage of this protein. Some reports subse-
quently conﬁrmed that this phosphorylation, mediated
by JNK3, regulates APP cleavage by inducing the
amyloidogenic processing of the protein, while JNK
inhibition by blocking APP phosphorylation is reduc-
ing the rate of amyloidogenic processing in favor of
the non-amyloidogenic one in vitro further underlying
the important role of JNK3 in AD pathology [21, 23–
25]. Additionally, some more recent data demonstrated
the contribution of JNK3 on tau hyperphosphorylation
Last but not least the ablation of JNK3 protected
against neuronal death in a model of axotomy [16, 27]
a ﬁnding that opened important implications in the ﬁeld
of regeneration of the CNS.
Altogether these results indicate JNK3 as a speciﬁc
key modulator in stressed neurons and in degenerative
conditions in the CNS.
In fact, the restricted expression of JNK3 in the CNS,
together with its selective over-activation by stress-
stimuli (see Fig. 2), render JNK3 an important mediator
in stress-induced signaling during degeneration in the
nervous system and thus an attractive target for the
development of therapeutical strategies.
JNK SCAFFOLD PROTEINS
Scaffold proteins have no enzymatic activity but act
as central organizers of diverse signaling pathways.
These proteins can concentrate, isolate and accelerate
c-Jun, Jun D, ATF2,
Bcl-2, Bad, 14-3-3, etc
nerve growth factor deprivation
cardiac cell death
Fig. 2. Schematic representation of the different stress stimuli and
how they affect JNK signaling. Different stimuli that could acti-
vate JNK1,2&3isoforms. JNK3 is mainly modulated by CNS
stress stimuli while JNK1 and 2 are more implicated in insulin resis-
tance, autoimmune or inﬂammatory diseases and cancer [16, 18, 20,
72–77]. All JNKs exert their functions by acting on common targets
(only some representative examples are given). (Colours are visible
in the online version of the article; http://dx.doi.org/10.3233/JAD-
Scaffold proteins are also crucial for the function and
regulation of JNK signaling. The speciﬁcity of JNK
signaling is partially controlled by scaffold proteins
. Emerging evidence indicates that scaffold pro-
teins may provide critical tools for manipulation of the
“signalosome” and the cellular response to different
A number of JNK scaffold proteins have been identi-
ﬁed, these are: the JNK interacting proteins (JIPs) ,
IKAP, ␤-arrestin-2, POSH [28, 30–32,] and ﬁlamin
In this review we will focus our attention only on two
JNK’s scaffolds: the JNK-interacting proteins (JIPs)
and ␤-arrestin-2 [28, 34].
The JIP group of scaffold proteins is highly ex-
pressed in the brain . JIPs were initially identi-
ﬁed as proteins that bind with mixed-lineage protein
kinases (MLKs), MKK7 or MKK4 and JNKs . In
mammals, there are four genes encoding JIP family
members: JIP1, JIP2, JIP3 and JIP4. These proteins
are all related in structure.
Additionally, all JIPs have the JNK binding domain
(JBD) and link to the light chain of Kinesin-1 via the
tetratricopeptide repeat (TPR) domain .
JIP1 and 2 are very similar, they contain the SH3
and PTB domains and they can also hetero-dimerize
under certain conditions . On the other hand, JIP3
and 4 have in common the coiled-coil domain and the
trans-membrane domain .
636 X. Antoniou et al. / JNK3 in Neurodegeneration
JIP1, 2 and 3 aggregate three-kinase components
of the JNK cascade and facilitate signal transmission
in cells. Interestingly, despite the structural similarity
between JIP3 and JIP4, JIP4 does not activate JNK and
seems to be an activator of the p38 pathway .
JIPs may contribute to modulate stress-signals [39,
40] but also the growth cones of neurons  as well as
axonal transport , sprouting and regeneration .
More generally the JIP family, by regulating the
subcellular localization of JNK’s cascade via the
kinesin-1 motor, may also interfere with the local-
ization and trafﬁcking of molecules, like the APP,
that are strongly implicated in neurodegenerative
disease. In fact JIP-1 interacts with APP via the
phosphotyrosine-interaction-domain (PID)  and
regulates its trafﬁcking and processing [24, 25, 46].
Furthermore, JIP1 colocalizes with amyloid deposits
and neuroﬁbrillary tangles in AD patients .
The ␤-arrestin family consists of four members:
␤-arrestin from 1 to 4, that are almost exclusively
expressed in the retina, and ␤-arrestin1 and 2 (also
known as arrestin 2 and 3 respectively) that are ubiq-
uitously expressed .
Initially ␤-arrestins were recognized as mediators of
G-protein-coupled receptor signaling. It is now known
that ␤-arrestins bind to G-protein-coupled receptors
(GPCRs) following ligand engagement and phos-
phorylation by GPCR kinases (GRKs). The adapter
proteins block the interaction of GPCRs with het-
erotrimeric G proteins and may induce receptor
internalization and sequestration in endosomes. The
␤-arrestins molecules have important functions in the
termination of heterotrimeric G protein activation by
However, ␤-arrestins may also recruit other sig-
nalling modules. Presently we know that they can act
as scaffolds for the mitogen-activated protein (MAP)
kinase signaling pathways , including ERK, p38
and JNK signaling pathway .
Notably, ␤-arrestin-2 acts as a scaffold of the JNK
signaling pathway and more speciﬁcally of JNK3.
In neurons, ␤-arrestin-2 binds to JNK3 and recruits
the signal-regulating kinase 1 (ASK1) and mitogen-
activated protein kinase (MAPK) kinase 4 [32, 51].
Importantly, ␤-arrestin-2 has a unique characteristic:
although it can bind to all JNK isoforms through the
common docking motif, binding to the N-terminus of
JNK3 leads to its speciﬁc activation without affecting
JNK1 and 2 activity . This is of relevant interest in
the CNS where JNK3 is highly expressed.
Moreover ␤-arrestins were recently designated as
important adaptors that link receptors to the clathrin-
dependent pathway of internalization . For this
it has been proposed that ␤-arrestin-2 may also con-
tribute to the regulation of synaptic receptors.
Together, these studies establish that ␤-arrestin-2
represents an important scaffold protein of the JNK3
cascade in the CNS.
PROTEIN SCAFFOLDS SPECIFICITY,
LOCALIZATION AND BINDING AFFINITY
An open question on the JNK3 signaling pathway is
how a particular stimulus elicits the correct response.
The JNK3 speciﬁcity is remarkable when one consid-
ers the diverse range of cellular responses that JNKs
mediate in the CNS (from growth to death).
Spatial and temporal changes of JNK3 activation
may affect the neuronal response and the scaffolds
proteins provide one mechanism by which this can be
In fact scaffolds facilitate interactions and propaga-
tion of the signal inside cells but they also sequester
the same kinase from other pathways thus preventing
cross talks between pathways . This also implies
that a scaffold protein can direct the activation of a
singular signal module in a particular cellular compart-
ment (nucleus, mitochondria, axon, synapses) [54, 55]
and subsequently lead to a powerful effect/modulation
within intracellular domains without affecting the total
activation inside the cell.
In polarized cells such as the neurons, scaffold
proteins may make the difference in regulating the
signaling response to a stimulus.
For instance, JNK3 speciﬁcity in neurons could be
modulated by both JIPs and ␤-arrestin-2. These two
scaffold proteins may have different localization inside
neurons [11, 56] and this can result in different reg-
ulation of the JNK modules. Moreover the different
binding afﬁnity that JIP1 and ␤-arrestin-2 may have for
the JNK isoforms can provide different signalosome
It has been proven that JIP1 links preferentially
MLK3, MKK7 but also MKK4 and all JNKs (JNK1-
2-3) , while ␤-arrestin-2 assembles AKT, MKK4
and JNK3. The different partners would suggest that
these scaffolds are regulating very different cellular
responses but also distinct signalosome inside diverse
X. Antoniou et al. / JNK3 in Neurodegeneration 637
The combination of extracellular signals, com-
partmentalization and molecular scaffolds creates an
intricate system utilized by neurons to regulate their
response to the environmental signals.
JNK SCAFFOLDS AS THERAPEUTIC
Due to their key role in neurodegeneration, JNK sig-
naling pathways have been the targets for the design of
pharmacological and potentially therapeutical agents.
Many chemical compounds have been generated (such
as SP600125, CC-401, CEP-1347) that block JNK
activity by interfering with the ATP catalytic pocket
or on upstream activators . Such inhibitors have
been proven useful for elucidating the role of JNK sig-
naling in neurodegeneration and some have entered
clinical trials (CC-401 developed by Celgene), how-
ever a more detailed analysis is beyond the scope of
Other type of inhibitors were subsequently designed
that instead interfere with the protein substrates and are
better known as cell penetrating JNK inhibitor peptides
(CPPs). These peptides share one characteristic: they
derive from the JIP scaffold protein. Of those the most
studied ones are: TAT-c Jun peptide, TI-JIP, L-JNKI
and D-JNKI1 [58–60].
JIP1 SCAFFOLD PROTEIN: THE CELL
PERMEABLE JNK INHIBITOR PEPTIDE
Knowledge on the JIP1 scaffold protein and its mode
of action led to the production of the most speciﬁc and
strong JNK inhibitor.
As already mentioned, JIP1 presents a consensus
sequence, the JBD motif, that is the same domain that
JNK uses to link c-Jun . This motif is a natural
blocker of JNK activity and in fact its over-expression
prevents apoptosis . Successively the JBD of JIP1
has been engineered as a cell permeable inhibitor pep-
tide namely D-JNKI1 .
This inhibitor is very strong and selective on JNKs
and differs from all common chemical inhibitors. In
particular, D-JNKI1 inhibits JNK1, JNK2 and JNK3
with Kinhibition values of 3.3 M, 430 nM, and 540nM
respectively (Dr. Sylvie Guenat, Xigen, personal com-
munication). It should also be noted that D-JNKI1
prevents partially JNK action by blocking the access of
all three JNK isoforms to its JBD-dependent substrates
Fig. 3. Schematic simpliﬁed diagram of D-JNKI1 peptide mode of
action. The JIP-1 scaffold protein interacts with JNK via the JNK
binding domain, a binding motif that is present in a number of JNK’s
targets. Following a stimulus, JIP1 (red shape) acts by recruiting
MLK3, MKK7 and JNK (blue shapes). Black arrow indicates the
JBD20 on the JIP scaffold protein (in green oval shape). The inhibitor
peptide (green oval shapes) acts by blocking the access of JNK to
JIP1 and to all its JBD-dependent substrates. (Colours are visible
in the online version of the article; http://dx.doi.org/10.3233/JAD-
and thus by inhibiting protein-protein interactions
mediated by the JBD domain (Fig. 3).
To further determine the speciﬁcity of the peptide
in blocking JNK action, we characterized the effects
of the peptide on the activity of 40 different kinases
(10 M peptide, 10 M ATP) towards their respective
substrates in a cell free system. It did not interfere with
the activities of the other kinases [62, 63] proving its
The protective action of D-JNKI1 has subsequently
been tested in several experimental models of disease
including cerebral ischemia [62, 64], auditory hair cell
loss , spinal nerve legation , viral encephali-
tis , myocardial ischemia-reperfusion injury ,
TBI  and in intra-timpanic treatment after acute
acoustic trauma . In addition we were able to show
that D-JNKI1 is able to interfere with AD pathogen-
esis and more speciﬁcally with APP phosphorylation
in cortical neurons as well as in an AD in vitro model
[24, 25], underlying the potential application of this
inhibitor in AD models.
Due to the very promising results achieved by D-
JNKI1 administration in several experimental models,
the efﬁcacy of this drug is currently at clinical phase
I/II trials in Switzerland and France (see web site:
638 X. Antoniou et al. / JNK3 in Neurodegeneration
It should be noted however that D-JNKI1 treatment
provides only a transient pain relief after spinal nerve
ligation, and no protection in myocardial ischemia-
reperfusion injury when administered at the time of
Altogether these reports underline the powerful pro-
tective action of D-JNKI1 in the CNS as opposed to
STRATEGIES TO IMPROVE JNK
JNK inhibitor compounds still have some limita-
tions. Chemical agents are too general, and they lack
selective inhibition of single signaling pathways. CPPs
are more speciﬁc, allowing inhibition of speciﬁc pro-
tein interactions. Still, today’s CPPs lack tissue and
isoform speciﬁcity. Furthermore, because JNKs regu-
lates myriad cellular functions, inhibiting total JNK
activity is likely to affect multiple processes, some
not linked to the patho-physiology of diseases. This
could probably generate unwanted side-effects, espe-
cially when targeting chronic conditions. Therefore,
new approaches are being explored to enhance thera-
peutic speciﬁcity of JNKs inhibitors.
JNK-protein scaffolds remain conceptually attrac-
tive therapeutical targets for a number of reasons. In
particular, scaffolds can regulate the localization of
many JNK’s components. Thus modulation of scaf-
fold proteins may allow regulation of the JNK action,
directing the cellular response to a particular func-
tion without inﬂuencing global JNK activity in the
neuron as a whole. Additionally by targeting the scaf-
fold protein, inhibition of JNK signaling in a speciﬁc
cellular compartment can be achieved and provide fur-
ther speciﬁcity. Last but not least, speciﬁcity could be
accomplished by targeting only JNK3 and not JNK1
and JNK2. Such an approach is particularly appealing
since JNK3 is responsible for many neurodegenerative
mechanisms and is highly expressed in the CNS.
In light of these data, the interaction between ␤-
arrestin-2 speciﬁcally with JNK3 represents a new and
interesting possibility to develop a speciﬁc inhibitor of
JNK3 to combat neurodegenerative disorders.
␤-ARRESTIN-2 SCAFFOLD: STRATEGY
TO DEVELOP THE MINI-␤-ARRESTIN-2
According to the literature, ␤-arrestin-2 is able to
speciﬁcally bind only JNK3 and not JNK1 and JNK2,
this opened the perspective of designing a JNK3 spe-
ciﬁc competitor peptide. Miller and colleagues 
showed that the ␤-arrestin-2 region important for this
interaction is mapped in the C-terminal region of
the protein that is arranged to form an antiparallel
eight-stranded ␤-sandwich. In particular they found a
short sequence in this region that is very similar to
the conserved docking motif present in many JNK
Kinase-binding proteins (D-domain) . Guo and
collaborators mapped the residues of JNK3 essen-
tial for the binding to ␤-arrestin-2 that correspond
to nine residues of the non-conserved N-terminus of
JNK3 . Moreover, this group demonstrated that
JNK3 does not directly bind to the putative D-domain
of ␤-arrestin-2 but instead binds in another portion
of the C-terminal region . However, residues
within the D-domain determine the speciﬁcity of ␤-
arrestin-2 binding to JNK3 and in particular they
underline the importance of Ser198 in ␤-arrestin-2
In the human JNK3 and ␤-arrestin-2 protein-protein
interaction, the structural and functional properties of
the surfaces are known or can be inferred using molecu-
lar modeling strategies, thus providing the opportunity
for setting up a possible inhibition strategy. Regret-
tably the development of small molecules, capable
of modulating such interaction, is tricky because the
design of an inhibitory compound able to bind ten
residues, i.e. the interacting sequence of the JNK3 N-
terminal tail, is a very hard task. Indeed, up today, to
hypothesize which will be the JNK3 N-terminal tail
conformation, when this portion of the protein is in
contact with ␤-arrestin-2, is over the reasonable lim-
its of the modeling. On the other hand, the ﬂexibility
and plasticity of the amino acids building blocks can
inspire other strategies in the development of a novel
Our suggestion is to generate a JNK3 inhibitor pep-
tide by focusing on the natural JNK3 interactor protein
␤-arrestin-2. We propose to reduce, as much as pos-
sible, the sequence of this protein to create a mini
␤-arrestin-2 able to fold, as observed in the complete
structure, maintaining its recognition capability. Noth-
ing indeed is more suitable for the interaction than
the JNK3 co-evolved molecular partner. The natural
strategy of recognition obviously should be separated
from the whole structure-function of the ␤-arrestin-2
machinery. As is known, the protein modeling strat-
egy enhances its achievements when it emulates the
structural features applied by the natural molecules
and this suggestion, although very complex and not
without uncertainties, respects this dogma.
X. Antoniou et al. / JNK3 in Neurodegeneration 639
One of the most intriguing open questions is to
understand how JNK can induce a speciﬁc response to
a particular stimulus, considering the different cellular
functions that this enzyme can control. Scaffold pro-
teins may be responsible for the speciﬁc regulation of
JNK’s functions, functions that may be very important
in some pathological conditions.
In fact some compounds, D-JNKI1 (XG-102 by
Xigen) and CC-401 (by Celgene) that inhibit the JNK
pathway have been successful and are progressing in
clinical trials. Still it is difﬁcult to predict potential
side-effects of this systemic inhibition and for chronic
Transgenic knockouts of JNK isoforms have pro-
vided crucial insights into the roles played by each JNK
isoform. It has been established that JNK1 and JNK2
have important roles in the modulation of immune
cell function and in the development of the embry-
onic nervous system. A study using JNK1 knockout
mice demonstrated that JNK1 has a regulatory role
and maintains physiological functions in the CNS,
while JNK2 knockout established that JNK2 may
additionally participate in some physiological func-
tions and in particular in the Long Term Potentation
(LTP). JNK3 seems to be more involved in over-
activation of JNK after stress-stimuli in adult brain
(ischemia, PD, AD, hypoxia, epilepsies). If JNK1, 2
are more implicated in the regulation of physiological
processes while JNK3 is more responsive to stress pro-
cesses the development of a selective JNK3 inhibitor
is preferable for the treatment of neurodegenerative
We consequently think that an important future chal-
lenge will be to increase tissue and isoform speciﬁcity
of JNK inhibition. The fact that JNK3 is speciﬁcally
expressed in the CNS and activated by stress-stimuli
renders it an attractive, and potential target for treating
many different neurodegenerative mechanisms form
acute (stroke) to chronic disease (AD and PD).
We speculate that JNK3 speciﬁc inhibition will
reduce the possible side-effects of a systemic JNK
inhibition and is more appropriate for the treatment
of neurodegenerative diseases in the adult CNS.
Considering the diverse neuronal functions that are
regulated by JNK3, its inhibition will also help us to
understand better the speciﬁc response of this enzyme
in the brain. In fact until now it is very difﬁcult to
discriminate against the 10 different isoforms of the
JNK family, which are formed by alternate slicing of
the three genes, Jnk1, Jnk2, Jnk3 . This is partially
because although the isoforms differ somewhat in their
substrate speciﬁcity in vitro  in vivo, JNK isoforms
share many common substrates (see Fig. 1 and 2).
Scaffold proteins and in particular ␤-arrestins are the
only known modulators of JNK3 speciﬁc activation
described in the literature. Targeting the ␤-arrestin-
2/JNK3 interaction by using this regulatory site, might
be one way to improve biological selectivity. In fact,
such inhibition acts not by blocking the active site of
this signaling enzyme (ATP pocket), but by inhibiting
interactions with substrates and scaffolding proteins.
Focusing on ␤-arrestin-2/JNK3 interaction will thus
prevent only partially JNK3 action and may result in
preventing just the pathological activity with regard to
some substrates but not others.
However, the hypothesis that targeting such sites
might lead to the design of inhibitors with improved
efﬁcacy and performance, while appealing, remains
Despite the complexities of this ﬁeld, JNK3 speciﬁc
inhibitor represents an attractive target for pharmaco-
CONFLICT OF INTEREST
Authors declare no potential conﬂicts of interests.
This was supported by the Marie Curie Industry-
Academia Partnerships and Pathways (IAPP) cPADS.
Special thanks to Architettura Laboratorio Commu-
nication and to Daniele Cardinetti for the graphics
Authors’ disclosures available online (http://www.j-
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