Signal-transduction pathways relay signals within cells
through a cascade of phosphorylation and dephosphory-
lation events executed by kinases and phosphatases,
which leads to gene transcription programmes that are
appropriate for the stimulus encountered. For immune
cells, these stimuli commonly include cytokines, chemo-
attractants, reactive oxygen species, antigen–antibody
complexes, and pathogen-associated molecules that
engage toll-like receptors. Signal-transduction pathways
facilitate appropriate immune responses to infectious
agents, but also operate during inappropriate inflam-
matory responses, such as in rheumatoid arthritis and
asthma. Therefore, pharmacological interruption of
certain signal-transduction molecules could prove
effective for modifying inappropriate cellular immune
responses. Indeed, numerous MAPK (mitogen-activated
protein kinase) pathway inhibitors, particularly p38
(also known as MAPK14) MAPK inhibitors, are currently
in clinical trials for chronic inflammatory diseases1.
Inhibitors of other pathways, such as the nuclear factor-κB
(NF-κB) pathway, are also showing promise in clinical
trials2. Also noteworthy is the calcineurin phosphatase
inhibitor cyclosporin — which regulates NFAT (nuclear
factor of activated T cells) signalling and has proved to
be a highly successful immunosuppressant for allo-graft
rejection and inflammatory disorders, particularly
psoriasis2,3 — and of course blockbuster drugs such as
the tyrosine kinase inhibitor imatinib (Gleevec; Novartis).
Finally, glucocorticoids that are used widely to treat various
inflammatory conditions have anti-inflammatory effects
that are due in part to the induction of dual-specificity
phosphatase 1 (DUSP1), a regulator of the MAPK path-
way that negatively regulates pro-inflammatory gene
expression in macrophages4,5. New ways of thinking about
signalling pathway dynamics and the elements that regu-
late them, such as phosphatases, will offer opportunities
for the manipulation of immune responses.
Until recently, the protein kinases rather than the
phosphatases have enjoyed the limelight as important
regulators of signalling cascades in immune cells, and
hence as drug targets. This can be explained partly by
the discovery of kinases around 10 years before the phos-
phatases. However, the phosphatases are now recognized
as powerful and even dominant controllers of many
biological processes. The DUSPs, a subclass of protein
tyrosine phosphatases that specifically dephosporylate
threonine and tyrosine residues on MAPKs and render
them inactive, represent exciting new drug targets
for both positive and negative regulation of immune
responses. By virtue of their dual dephosphorylating
capabilities, DUSPs are now recognized as key players in
inactivating different MAPK isoforms, and understand-
ing their precise physiological roles presents an impor-
tant challenge and opportunity for drug development.
Program, The Garvan
Sydney, NSW 2010, Australia.
‡Merck Serono Research
Centre, Merck Serono S.A.,
9 Chemin des Mines,
Geneva 1202, Switzerland.
Correspondence to K.L.J.
A chronic, inflammatory
autoimmune disorder in which
leukocyte invasion of the
synovial lining and hyperplasia
of resident synoviocytes
occurs. The ensuing
overproduction of cytokines
and other soluble mediators
results in neovascularization,
cartilage destruction, bone
erosion and anarchic
remodelling of joint structures.
Targeting dual-specificity phosphatases:
manipulating MAP kinase signalling
and immune responses
Kate L. Jeffrey*, Montserrat Camps‡, Christian Rommel‡ and Charles R. Mackay*
Abstract | Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine
phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-
activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases
(MKPs). The regulated expression and activity of DUSP family members in different cells and
tissues controls MAPK intensity and duration to determine the type of physiological
response. For immune cells, DUSPs regulate responses in both positive and negative ways,
and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of
immune responses. From a drug discovery perspective, DUSP family members are promising
drug targets for manipulating MAPK-dependent immune responses in a cell-type and
disease-context-dependent manner, to either boost or subdue immune responses in cancers,
infectious diseases or inflammatory disorders.
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© 2007 Nature Publishing Group
A state of T-cell
stimulation with antigen.
T-cell anergy can be induced
by stimulation with a large
amount of specific antigen in
the absence of the
engagement of co-stimulatory
The deletion of self-reactive
thymocytes in the thymus.
Thymocytes expressing T-cell
receptors that strongly
recognize self peptide bound
to self MHC molecules
undergo apoptosis in response
to the signalling generated by
In this Review, we will discuss the role of DUSPs in
regulating MAPKs and immune responses and suggest
that targeting DUSPs may provide a more tissue-specific
and controlled therapeutic approach for controlling
MAPK-dependent cellular responses.
MAPKs and immune responses
The evolutionarily conserved MAPK pathway is present
in yeast and all other eukaryotes and is a major signalling
pathway in many cell types, particularly in immune cells6–9.
MAPKs are fundamental regulators of most immune
cell functions, including proliferation, differentiation,
survival and apoptosis, chemoattraction, and production
of inflammatory mediators6,9 (BOX 1). Disruption of one
or more of these cellular processes is a viable strategy for
combating inflammation and other immune disorders.
The roles of extracellular signal-regulated kinase (ERK),
p38 and c-Jun N-terminal kinase (JNK) isoforms of
MAPKs have been studied extensively in T cells, in
particular for T-cell development in the thymus10–13,
CD4+ T-cell differentiation to T helper 1 (TH1) and TH2
cells14–16, and T-cell proliferation. ERK has a proposed
role in T-cell anergy, promotes TH2-cell differentiation and
is needed for thymocyte maturation6,15. p38 MAPKs con-
trol production of interferon-γ (IFNG)14 and apoptosis of
certain T-cell subsets17. JNK1 (also known as MAPK8)
and JNK2 (also known as MAPK9) cooperatively control
T-helper-cell differentiation and cytokine production.
JNK2 is important for thymocyte negative selection, JNK1
has a negative effect on TH2-cell differentiation, whereas
JNK2 promotes TH1-cell differentiation6,15.
MAPKs are pivotal for processes that are central to
inflammatory responses such as cytokine production by
immune cells. This is achieved through the activation of
nuclear transcription factors, and through the stabiliza-
tion of inflammatory cytokine mRNA using adenosine-
uridine-rich elements (AREs)18,19. The MAP3K (MAPK
kinase kinase) TPL2 (also known as MAP3K8) and ERK
promote the transport of mRNA for tumour-necrosis
factor (TNF) from the nucleus to the cytoplasm but
have no effect on transcription of the TNF gene or on
the stabilization of TNF mRNA following toll-like
receptor 4 (TLR4) activation in macrophages19. p38 is
probably involved in the initiation of TNF translation
by the ARE region20. p38 also promotes transcriptional
activation of the interleukin genes IL1A and IL1B in
lipopolysaccharide-stimulated macrophages21, and
specifically regulates IL-12 (REF. 6) and IFNG14 pro-
duction in certain cells. JNK is also required for the
production of many cytokines, including type I IFNs
and IL-6, following its activation by lipopolysaccharide
or inflammatory cytokines6.
MAPKs are also important signalling elements for
cell migration after chemoattractant receptor activation.
JNK regulates paxillin, a cytoskeletal protein involved
in cell motility, to control cell migration22; p38 mediates
signalling through both C5AR1 (the complement com-
ponent C5a receptor 1) and CXCR4 (CXC-chemo kine
receptor 4)23 and controls cell directionality through its
downstream substrate MAPK-activated protein kinase 2/3
(MAPKAPK2/3)24. Similarly, ERK governs cell motility
through its ability to control both cell adhesion and
detachment at the trailing end25. Therefore, MAPKs par-
ticipate in one of the essential processes of the inflam-
matory response: the recruitment of leukocytes to the
Finally, the survival and lifespan of leukocytes are
carefully controlled by signals that are regulated by
MAPKs to ensure that the effects of inflammatory
mediators do not harm the host. In general, ERK1/2
promotes cell survival whereas p38 and JNK promote
apoptosis. However, this dichotomy is not absolute given
that the actual role of each MAPK is highly cell-type and
context dependent7. p38 specifically promotes cell death
of CD8+ T cells but not CD4+ cells through suppressing
B-cell CLL/lymphoma 2 (BCL-2). JNK is involved in Fas-
mediated cell death as well as Bax-mediated apoptosis by
releasing Bim to suppress the pro-survival factors BCL-2
and BCL-XL, while ERK-mediated phosphorylation of
Bim inhibits its pro-apoptotic function and marks it for
The physiological role of MAPKs in immune
responses is unravelling with the aid of kinase-specific
inhibitors and through genetic manipulations, and some
of the phenotypes of various MAPK-deficient mice are
listed in TABLE 1. These phenotypes have led numer-
ous companies to develop inhibitors of various MAPK
pathway members1,2 (Supplementary information S1
(table)). However the roles of MAPKs in different
leukocyte cell types still need to be clearly established.
For instance, less information is available on the role of
MAPKs in mast cells, dendritic cells, neutrophils and
B cells, as well as on the different T-cell subsets, such
as T-follicular helper cells and the inflammation-related
T helper 17 cells. Recently, a role for ERK was estab-
lished for integrating signals in TLR4-driven plasma cell
differentiation27, but B-cell phenotypes have yet to be
reported in MAPK-deficient mice.
The complex web of MAPK signalling
MAPK signalling was initially viewed as a relatively simple
linear receptor-to-nucleus pathway, but new knowledge
from the last 5 years demonstrates a reversible phosphory-
lation of kinases in multiple cascades controlled by many
feedback loops and much crosstalk with other path-
ways28–31. Therefore, the many kinases form a complex
and sophisticated web to finely control cellular functions
(FIG. 1). This may raise unexpected complications for
single-kinase inhibition and may be a valid explanation
for why many kinase inhibitors have failed in clinical
trials (Supplementary information S1).
The intensity, duration and subcellular localization of
the MAPK signal, as well as redundancy, feedback and
crosstalk with other signalling molecules, cooperate to
determine the specific cellular response. Hence there are
multiple control points for MAPK activation that need to
be considered. The distinct biological outcomes are often
achieved purely because of the duration of MAPK activity,
as immediate early genes act as sensors to the MAPK
signal32. Spatial arrangement and compartmentalization
are also important aspects, whereby the nucleus acts as
an essential site for signal termination by sequestering
392 | MAY 2007 | VOLUME 6
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A second-order reaction
depends on the concentration
of one second-order reactant
or two first-order reactants.
A kinase acting on a MAPK is
a second-order reaction as it
requires the MAPK and ATP
(that is, two first-order
the MAPKs away from their cytoplasmic activators and
aligning them with nuclear phosphatases33,34. In addition,
spatial localization of MAPKs also determines the sensi-
tivity of the MAPK module to various stimuli34,35, as well
as the specific cellular outputs by subcellular-specific
substrates36. As will be discussed below, the DUSPs also
have an important role in MAPK localization.
There is also now an increased understanding of the
feedback loops28,37 and crosstalk within the MAPK path-
way and with other pathways that assist in the amplifica-
tion, diversification and termination of the MAPK signal.
Feedback and crosstalk have major implications for the
development of MAPK inhibitors as anti-inflammatory
agents. For example, the upstream TAK1-binding
protein 1 (TAB1; also known as MAP3K7IP1) is directly
phosphorylated by p38α and then downregulates TAK1.
This feedback control limits the activation of p38, as
well as downstream components such as JNK and IKK
(inhibitor of NF-κB kinase kinase), and synchronizes the
three pathways29. However, inhibition of p38 disrupts
this feedback and causes the activation of the JNK and
IKK pathways, which themselves are pro-inflammatory
and may lead to unwanted side effects29. Examples of
crosstalk include the ERK-dependent inhibition of p38
following exposure to transforming growth factor-β1
(TGFB1) to inhibit inflammatory cytokine production38
and the sustained activation of JNK, which blocks ERK
activation in response to mitogenic stimuli30,31,39. MAPKs
also display crosstalk with other pathways, such as the
JAK–STAT (Janus kinase–signal transducer and activa-
tor of transcription) and PI3K (phosphatidylinositol
3-kinase) pathways40,41. These all have major implications
for successfully targeting individual MAPKs for thera-
peutic use. Inhibiting an individual kinase may disrupt
critical feedback loops and crosstalk, which may have
unexpected consequences. There is evidence for this in
the context of p38 inhibitors and an observed liver toxicity
in clinical trials (Supplementary information S1).
Phosphatases versus kinases in MAPK regulation
Although protein phosphatases have been considered by
some as simply ‘fuse switches’ to prevent system overdrive,
kinases are inactivated even in the presence of continuing
stimuli, which suggests that phosphatases are pivotal in
regulating the duration and strength of kinase activation
to control the required cellular response. From a biochem-
ical perspective, the enzymatic power of a phosphatase is
as much as 100 to 1,000 times as great as that of a kinase,
owing to the fact that kinases require ATP and therefore
use a second-order reaction, whereas dephosphorylation is
direct42. Hence it is conceivable that constrained signal
transduction does not occur through kinase activation,
but rather by the control of phosphatase expression
and activity. In support of this, phosphatases, rather
than the kinases, appear to have much more dynamic
regulation, both in their expression and in their activity.
Box 1 | DUSPs, MAPKs and the immune response
Generating mutant mouse strains through genetic deletion has helped to determine individual roles for mitogen-
activated protein kinases (MAPKs) and some dual-specificity phosphatases (DUSPs) in both health and disease.
Many of these in vivo studies have revealed surprising complexities. The use of unconditional, global knockouts, while
instructive, is often complicated, for instance by compensatory signalling elements or embryonic lethality. Conditional
knockouts that are temporally and spatially controlled should be more informative. In addition, limitations of the
immune cell types that are studied or reported in MAPK and DUSP knockout systems also leave holes in our
understanding of the role of individual DUSPs and MAPK isoforms in all immune cells. It is likely that DUSP and MAPK
members have differing influences in various cells and generalizations that are made from data in one cell type should
be avoided. Nevertheless, much information has been gleaned from global knockouts of the various MAPKs and DUSPs,
which supports in vitro data on MAPKs and DUSPs in immune responses. However, in some cases, surprising and
unpredicted roles for MAPKs and DUSPs in a whole physiological setting have been revealed. A summary of MAPKs
and their associated DUSPs and immune responses are shown in the accompanying table. For phenotypes of DUSP
knockouts in the immune system refer to TABLE 2.
MAPK MAPK roleSubstrate for References
Cytokine production (TNF M∅), thymic selection, TH2
differentiation, prevention of plasma cell differentiation,
survival, cell-cycle control
IFNG production (TH1 cells), TNF translation, Il1a and
Il1b transcription (M∅), IL-12 production (M∅ and DCs),
chemotaxis to C5a and CXCL12, apoptosis (CD8+ cells)
DUSP1, DUSP2, DUSP4,
No major role in the immune system 129
Knockout viable, no immune investigation 130
CD8+ proliferation, thymocyte survival, IL-2 production,
inhibits TH2 differentiation
DUSP16, DUSP18, DUSP22
JNK2 Negative to CD8+, proliferation, negative to IL-2,
promotes TH1 differentiation
CXCL12, chemokine (C-X-C) motif ligand 12; DC, dendritic cell; ERK, extracellular signal-regulated kinase; IL, interleukin; IFNG,
interferon-γ; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; M∅, macrophage; TH2, T helper 2; TNF, tumour-necrosis factor.
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Table 1 | The DUSPs that regulate MAPK activity
in KO mice
of KO mice
Human disease Small-molecule
No change in
ERK, JNK and p38
↑ p38 and JNK in
change in ERK in
↓ ERK and p38 in
mast cells, ↑ JNK
and mast cells
↑ ERK and JNK
in HeLa cells
(↓ IL-12), ↑ sepsis
↓ survival of mast
cells, ↓ arthritis31
↑ Breast cancer99,
growth of other
DUSP2 Nuclear ERK, p38 >
ERK > JNK >
Cell-cycle arrest at
G1-S and G2-M70
NDNU-126 (REF. 151),
RK-682 (REF. 153)
DUSP4 MKP2, hVH2
DUSP6 Cytosolic ERK >
JNK = p38
↑ ERK in embryos
stosis, hearing loss159
↑ In acute
NSC 45382, NSC
295642, NSC 357756
(REF. 80), B59
(REF. 75), HB5
ERK > p38α
JNK > p38 >
JNK = p38
No change in ERK,
JNK and p38 in
and ES cells
↑ JNK in T cells,
no change in p38 in
JNK = p38 >
↑ Cytokines in
T cells, ↓ proliferation
in T cells, ↓ EAE61
ND NDND ND
ERK, JNK, p38
p38 or ERK1
ES cells, ↓ JNK
pro duced by Ceptyr
of certain cancer
↑, increased; ↓, decreased; CIA, collagen-induced arthritis; DUSP, dual-specificity phosphatases; EAE, experimental autoimmune encephalomyelitis; ERK, extracellular
signal-regulated kinase; ES, embryonic stem; JNK, c-Jun N-terminal kinase; KO, knockout; MAPK, mitogen-activated protein kinase; MKP, mitogen-activated protein
kinase phosphatase; ND, no data; RNAi, RNA interference.
394 | MAY 2007 | VOLUME 6
© 2007 Nature Publishing Group
Strong transcriptional induction and protein stabilization
of phosphatases — both a result of MAPK activity43–47
— as well as the control of their activity by reversible
oxidation48,49 are illustrative of this (FIG. 2). Interestingly,
a computational analysis of the MAPK system suggests
that DUSPs, and not the kinases, dictate the extent of
MAPK phosphorylation following cellular activation50.
Also, the influence of DUSPs extends beyond that of a
dephosphorylating role, as some can shuttle or anchor
MAPKs between the cytoplasm and nucleus51,52.
The superfamily of tyrosine phosphatases
Phosphatases are enzymes that can hydrolyse the phos-
phoester bonds on protein, lipid or small-molecule
substrates. MAPKs are inactivated completely by dephos-
phorylation of either the tyrosine or threonine residues,
or both53. Many phosphatases are dedicated to dephos-
phorylating one or both of the phosphosites in the active
site of MAPKs to control the magnitude and duration of
MAPK activity (outweighing the number of activating
kinases). In intact cells, dephosphorylation and inacti-
vation of MAPKs occurs with kinetics that range from
minutes to several hours depending on the cell type and
activating stimulus54. The family of cysteine-dependent
protein tyrosine phosphatases (PTPs) comprises 106 genes
in humans and shares a canonical C(X)5R motif in their
active sites. Based on structural homology and substrate
preference, this superfamily is divided into seven catego-
ries55,56 (FIG. 3; see also the Protein Tyrosine Phosphatases
web site). The phosphatases that can inactivate MAPKs
include: the PTPs that hydrolyse phosphotyrosine
residues on activated MAPKs; the serine/threonine phos-
phatases, referred to as protein phosphatases (PPs), that
dephosphorylate threonine residues; and the class I family
of DUSPs (also known as MAPK phosphatases, DSPs or
MKPs) that dephosphorylate phosphotyrosine and threo-
nine residues that are located in the same MAPK54,57–60
(FIG. 3). The class I family of DUSPs are further subcate-
gorized into CH2 (CDC25 homology)-motif-containing
MAPK phosphatases (MKPs), JSP1-like phophatases,
MKP6-like, VHR-like, slingshot-like and SKPR1/hyVH1
(FIG. 3). Historically, the PPs were among the earliest to
be identified (in the 1970s), followed by the PTPs (in the
1980s), and then by the DUSPs (1993 to present). Thus,
an understanding of enzymatic regulation is greatest for
the PPs, whereas knowledge about the mechanisms and
substrates of PTPs and DUSPs is still emerging.
The DUSPs form a structurally and functionally distinct
subclass among the many protein phosphatases present
in eukaryotic genomes. Of the 43 DUSPs depicted in
FIG. 2 a further subclass classification can be made that is
based on structural and sequence similarities. The class I
DUSPs regulate MAPK activity through ‘TXY-motif’
dephosphorylation and represent particularly important
negative regulators of MAPK signalling54,61–63 (TABLE 1).
At least 16 mammalian DUSPs that show desphospho-
rylating activity towards MAPKs have been identified to
date (TABLE 1). Of these 11 are ‘typical’ MKPs that contain a
CH2 motif for MAPK docking and comprise three major
subfamilies that are based on their sequence similarity,
substrate specificity and subcellular localization54,64–67
(TABLE 1). They all share common features, including an
extended active-site motif with high sequence similarity
to the corresponding region of the VH1 protein tyrosine
phosphatase that was isolated from vaccinia virus54. In
addition, their amino terminus contains a cluster of basic
amino acids as part of the kinase interactive motif (KIM).
The KIM confers substrate specificity and is the least
homologous region demonstrating individual substrate
The first subfamily comprises DUSP1, DUSP2,
DUSP4 and DUSP5. They localize to the nucleus, and
are induced by growth factors or stress signals. The pro-
teins consist of four exons, the positions of which are
highly conserved. In addition, the active site motif of all
four of these DUSPs is encoded within exon 4 and the
length of their exon 3 is identical, which is suggestive
of a common ancenstral gene64,67. The second subfamily
comprises DUSP6, DUSP7 and DUSP9. They consist of
3 exons, are cytoplasmic in their subcellular localization
and preferentially recognize ERK1 and ERK2 in vitro.
DUSP8, DUSP10 and DUSP16 make up the third sub-
group as they preferentially recognize JNK, p38 or both,
Of the ‘atypical’ DUSPs, many of which resemble
CDC14 cell-cycle phosphatases, approximately six have
activity towards MAPKs. DUSP3 (also known as VHR)
is an additional mammalian homologue of VH1 (REF. 68)
but lacks the required N-terminal motif for MAPK
binding and indeed appears to be relatively inactive
against MAPKs in vitro69. RNA interference of DUSP3
however had profound effects on the cell cycle mediated
by JNK and ERK70. Additional members of this class I
subfamily of DUSPs include stress-activated protein
kinase (SAPK) pathway-regulating phosphatase 1
(SKRP1), which lacks the CDC25 domain but contains
the conserved active-site sequence and can inactivate
JNK through its binding to the upstream JNK-activator
MKK4/7 (REFS 71,72).
Different DUSPs for different cell types
Multiple DUSPs probably act cooperatively in individual
cells to control MAPK activity. For instance, activated
macrophages express several DUSPs73. Nevertheless,
because the many DUSPs show different patterns of
tissue expression, transcriptional control, substrate spe-
cificity and subcellular localization, it is conceivable that
individual DUSPs regulate specific cellular responses in
certain cell types. Some DUSP family members show
restricted expression to certain tissue types. For instance,
DUSP2 is enriched in haematopoietic cells31,63,74; DUSP8
appears to be expressed predominantly in brain, heart
and skeletal muscle75; DUSP10 is expressed ubiquitously,
but is more abundant in cerebellum, skeletal muscle and
bone marrow, and is transcriptionally regulated in macro-
phages61,76; whereas DUSP9 is found only in placenta,
kidney and embryonic liver77,78.
The diverse expression patterns of the many DUSPs
in different immune cell types have been analysed
recently31,73,79. These data correlate well with previous
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Growth factors, mitogens,
FASL, UV, etc.
Raf-1, B-Raf, A-Raf
p38α, β, γ, δ
MTK1, DLK, TAO1/2
Cytokine production, apoptosis,
migration, proliferation, differentiation
c-Fos c-JunATF-2AP1 STAT1
p38α, β, γ, δ
MAPKAPK2, 3, 5
expression studies, and emphasize that the immune
cell expression patterns of some DUSPs are suggestive
of individual roles for these DUSPs in certain immune
responses. For example, DUSP1 is highly expressed
in neutrophils, macrophages and B cells, but is absent
from T helper cells. DUSP2 is largely absent from
non-activated leukocytes, but is highly expressed in
activated cells, especially mast cells, neutrophils and
B cells (TABLE 1). DUSP3 transcripts are expressed
abundantly in non-immune cells, which is suggestive
of a role outside the immune system. DUSP9 is high
in kidney (as previously described77) and intermediate
Figure 1 | The MAPK pathway and the role of DUSPs. The three main arms of the mitogen-activated protein kinase
(MAPK) pathway, ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38, that mediate
immune cell functional responses to stimuli through multiple receptors such as chemoattractant receptors, Toll-like
receptors and cytokine receptors are shown. The three-tiered kinase dynamic cascade leads to activated MAPKs
entering the nucleus to trigger immediate early gene and transcription factor activation for cellular responses such as
cytokine production, apoptosis and migration. Approximately 18 MAPK genes encompassing four subfamilies have
now been identified in mammalian cells137. The main classes of mammalian MAPKs consist of ERK1 and ERK2, and the
more recently identified larger kinases ERK3 (α and β), ERK4 (ERK1b), ERK5, ERK7 and ERK8; p38 MAPKs (p38α, β, γ, δ);
and JNKs, also known as stress-activated protein kinases (SAPK1, 2, 3) (for recent reviews see REFS 6,8,9,97,138,139).
All MAPKs, except the larger ERKs that remain less well characterized139,140, are activated by dual phosphorylation of
the threonine and tyrosine residues within a conserved ‘TXY’ motif in their kinase domain. A general feature of MAPK
pathways is the three-tiered kinase canonical cascade consisting of a MAPK, a MAPK kinase (MAP2K, MAPKK, MKK or
MEK) and a MAPK kinase kinase (MAP3K or MAPKKK)9,141. The existence of this tier is probably essential for the
amplification and tight regulation of the transmitted signal. Seven upstream MAP2Ks and 14 MAP3Ks have been
identified9,141,142. For receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs), MAPK cascade
activation is initiated by small GTP-binding proteins, STE20-like kinases or by adaptor proteins that transmit the signal
to MAP3Ks9. MAP3Ks then transfer the signal to MAP2Ks to induce MAPK activation. Thus, MAP3Ks provide some
stimulus specificity, creating independent signalling modules that may function in parallel, whereas the MAPKs carry
out the effector functions of each cascade, either through direct phosphorylation of effector proteins, such as
transcription factors, or activation of subordinate kinases, known as MAPK-activated protein kinases (MAPKAPKs).
Multiple dual-specificity phosphatases (DUSPs) specifically dephosphorylate the threonine and tyrosine residues on
MAPKs, rendering them inactive either in the cytoplasm or nucleus. DUSPs also assist in shuttling or anchoring MAPKs
to control their activity. Red arrows indicate feedback or crosstalk within the MAPK pathway.
396 | MAY 2007 | VOLUME 6
© 2007 Nature Publishing Group
in most leukocyte types. DUSP10 shows high expres-
sion in mast cells, is absent from plasmacytoid dendritic
cells, is intermediate in dendritic cells and TH1 and TH2
cells, and is high in skeletal muscle and liver. Indeed
only a limited number of DUSPs, usually only one or
two, show high expression in any single immune cell
type (TABLE 2). In addition to their differing patterns of
tissue expression, DUSPs show differing subcellular
localizations (that is, cytosolic versus nuclear), which
suggests that they regulate the activity of specific pools
Regulating DUSP expression and activity
An interesting feature of DUSPs is their tight and
sometimes rapid transcriptional induction by growth
factors or factors that induce cellular stress. Most
DUSPs are inducible genes with basal levels of DUSPs
being mostly low in unstressed or unstimulated cells67.
Nuclear DUSPs (DUSP1, DUSP2, DUSP4 and DUSP5)
show the most dramatic transcriptional regulation, at
least in leukocytes31. Some DUSPs serve as immediate
early genes following stimulation. DUSP1, DUSP2,
DUSP4 and DUSP7 are rapidly induced in response to
serum stimulation. This induction is also dependent
on MAPK activation and is thought to be a mechanism
for the attenuation of mitogenic signalling43,46,80. By
contrast, DUSP6, DUSP8, DUSP9 and DUSP10 are not
encoded by immediate early genes67,81. Different DUSPs
also respond to different stimuli. For example, DUSP1 is
induced by mitogens, oxidative stress, heat shock82 and
hypoxia83,84, whereas DUSP7 is induced only moderately
by serum and not by cellular stress80. Moreover, although
DUSP6 expression is not induced by either mitogens or
cellular stresses85,86, its expression can be increased by
agents that promote neuronal differentiation81. On the
other hand, DUSP2 is highly transcriptionally regulated,
but is exclusive to immune cells31.
An additional mechanism by which DUSPs can be
regulated is through their stabilization at the level of
protein expression, which is controlled directly by the
MAPKs. For example, DUSP1 is rapidly degraded soon
after induction. However, through a negative-feedback
mechanism, ERK can induce stabilization of DUSP1 by
direct phosphorylation, which leads to reduced ubiquityl-
ation and proteasomal degradation47. Interestingly, the
reverse also occurs whereby ERK, in cooperation with
the SCFSkp2 ubiquitin ligase, enhances polyubiquitylation
and proteolysis of DUSP1 as part of a positive-feedback
mechanism45. Furthermore, some DUSPs are activated
following binding to their respective substrates. DUSP6
experiences a 25-fold increase in catalytic activity when
complexed to its phosphorylated substrate, ERK2
(REF. 87). Similarly, DUSP1 catalytic activation is medi-
ated by physical interactions with ERK2, JNK1 and p38
in vitro88 and DUSP2 enzymatic activity, which is virtu-
ally inactive when alone in vitro, is also enhanced upon
binding to ERK2 through its N-terminal domain89,90.
Enzymatic deactivation of phosphatases also occurs
by the action of reactive oxygen species that have been
shown to reversibly oxidize the conserved catalytic site
cysteine in PTPs and inactivate their enzymatic activity49,91.
Indeed, TNF-induced cell death is promoted by reac-
tive oxygen species that specifically inhibit the cysteine
residue at the catalytic site of DUSPs, to increase JNK
activity48. Thus, in a manner analogous to reversible
phosphorylation, reversible oxidation provides another
mode of activation or deactivation of proteins following
certain cellular stimulations.
Regulating MAPK activity
Another function of DUSPs, in addition to their dephos-
phorylating activity, is the control of the subcellular
localization of MAPKs. For instance, certain DUSPs
regulate the cytoplasmic nuclear shuttling of MAPKs.
DUSP16, which contains both a nuclear localization sig-
nal and a nuclear export signal, can transport both p38
and JNK from the nucleus to the cytoplasm51. Similarly,
DUSP6, a cytoplasmic DUSP that contains a nuclear
export signal, causes the cytoplasmic retention of ERK2,
which is dependent on both its nuclear export signal and
its KIM motif that binds the MAPK52. These initial dis-
coveries may elucidate mechanisms that control MAPK
subcell ular localization and emphasize that DUSPs have
roles other than dephosphorylating MAPKs.
Substrate specificities of DUSPs
Assessing the precise substrate specificities for the
DUSPs has proved problematic, often because in vitro
assays do not always reflect physiological roles in vivo.
Importantly, however, DUSPs do appear to have pre-
ferred substrates. For example, DUSP6 is 100-fold
more active towards ERK2 than p38 or JNK85. Similarly,
DUSP9 seems to have a preference for ERK over other
MAPKs77. By contrast, DUSP8, DUSP10 and DUSP16
have little activity for ERK and seem to prefer JNK and
p38 kinases51,75,76,92,93. These reported in vitro substrate
preferences should be treated with some caution, as dif-
ferent cell types and stimuli regulate different MAPKs.
Thus, DUSP regulation of MAPKs may be cell-type and
In addition, although all DUSPs seem to have some
individual preference towards a MAPK, efficacies may
differ between two DUSPs. For example, although both
DUSP2 and DUSP4 have a preference for ERK in vitro,
DUSP4 dephosphorylates ERK much more efficiently
than DUSP2 (REF. 62). The substrate specificity of the
various DUSPs may reside in their heterogeneous
KIM docking site95. However, substrate availability
and access in certain cells types is another important
consideration. For instance, although Dusp10–/– T cells
had elevated JNK activity (as predicted from in vitro
studies), there was no change in p38 activity61; Dusp1–/–
macrophages had elevated p38 and JNK activity but no
change in ERK activity despite in vitro evidence that
demonstrates an equal preference for all three62,96,97;
DUSP3 had little activity towards MAPK in vitro, but
had elevated ERK and JNK activity following RNA
interference70; and Dusp2–/– macro phages and mast cells
showed a surprising reduction in ERK and p38 activity
but elevated JNK activity, highlighting the co-dependence
of certain DUSPs and the strong influence of MAPK
crosstalk31 (TABLE 1).
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© 2007 Nature Publishing Group
IEG induction and
formation of transcription
factor complexes such as
NFAT–AP1 or NFAT–CBP
Immediate early Intermediate
Physiological roles for DUSPs
Currently, the physiological roles of many of the
DUSPs are still largely unknown in vivo. Many have
shown correlation with multiple types of human can-
cers. Overexpression of the ubiquitous DUSP1, which
dephosphorylates ERK, JNK and p38 (REF. 62), has been
found in several malignancies, including breast and
prostate98,99. DUSP6 is hyper-methylated in pancreatic
cancer, which suggests that it could act as a tumour sup-
pressor100, whereas DUSP2 is increased in ovarian cancer
and a splice variant was found in leukaemia101,102. DUSP7
shows enhanced expression in myeloid leukaemia103,104,
whereas DUSP26 is overexpressed in, and promotes
growth of, anaplastic thyroid cancers105. DUSP1 expres-
sion is also inversely related to apoptosis106,107, although
DUSP1 deletion in mice initially yielded no obvious
pheno type with normal development and MAPK
activities in fibroblasts108. However, further studies
have shown elevated p38 activity in DUSP1-deficient
alveolar macrophages109, which suggests a potential
cell-type-specific activity for this DUSP.
Recently, four reports described that DUSP1 sup-
presses endotoxic shock in vivo via feedback control of
p38 and JNK activity96,97,110,111. Interestingly, although
Dusp1–/– macrophages, splenocytes and dendritic cells
showed an increase in cytokine production, which
demonstrates its negative control over this cellular pro-
cess, IL-12 production was specifically reduced, despite
similar levels in serum after lipopolysaccharide chal-
lenge, which suggests some positive regulatory activities
of DUSP1 (REFS 96,97). In addition, DUSP1 regulated
cytokine production in a temporally specific manner,
whereby negative regulation on cytokines was seen at
earlier time points following cellular activation, and
positive regulation was observed at later time points110.
A role for DUSP1 in controlling nuclear MAPKs and
metabolic homeostasis has also been observed. Despite
unimpaired insulin signalling and glucose homeostasis,
Dusp1–/– mice were resistant to diet-induced obesity due
to increased energy expenditure, but they developed
glucose intolerance112. DUSP9 is required for placental
development, but its absence appears not to influence
MAPK phosphorylation78. Interestingly, the placental
phenotype of Dusp9–/– mice highlights the need for fine-
tuning the MAPK pathway for proper placental develop-
ment. DUSP10 was shown to be an important regulator
of innate and adaptive immune responses mediated by
the attenuation of JNK activity61. Like DUSP1, DUSP10-
deficient mice revealed a potential for both positive and
negative regulation of cellular responses. Dusp10–/– mice
exhibited an expected increase in cytokine production
from macrophages after TLR stimulation, but also had an
unexpected reduction in proliferation of T cells and pro-
tection in a model of experimental autoimmune encephalo-
myelitis61. Dusp2–/– mice also had an unexpected and
complex phenotype. Activation levels of ERK and p38
actually decreased in the absence of DUSP2 in activated
macrophages and mast cells, but JNK increased. This
resulted in reduced inflammatory mediator produc-
tion from these cells, which could be rescued through
reconstitution with phosphatase-active DUSP2 (REF. 31).
Figure 2 | Regulation of DUSPs by MAPKs. In contrast to mitogen-activated
protein kinases (MAPKs) themselves, dual-specificity phosphatase (DUSP) expression
and activity are strongly regulated by three main mechanisms as shown in panels a–c.
a | The unique, strong, transcriptional activation of DUSPs to various stimuli either
through immediate early gene (IEG) activation (DUSP1, DUSP4, DUSP7 and DUSP2),
or by other transcription factors (DUSP6, DUSP9, DUSP10 and DUSP8) through
activity of MAPKs themselves. MAPK-dependent activation of E-box and AP2
transcription factors leads to DUSP transcription. MAPKs also promote the stability of
DUSP mRNA in the cytoplasm. b | Protein stability and catalytic activity of DUSPs is
highly regulated through binding to MAPK substrates in both negative and positive
ways. MAPK binding to DUSPs can increase protein stablility to provide feedback to
MAPK activity44. Sometimes however, as is the case for DUSP1, MAPK binding can
decrease protein stability and promote DUSP1 proteolysis through the ubiquitin
ligase SCFSkp2, thereby sustaining MAPK activity45. c | Reactive oxygen species (ROS)
that regulate some immune responses and activate the upstream kinase MAP3K5
(also known as ASK1) directly inactivate catalytic sites (at the conserved cysteine 257)
of DUSPs. d | The temporal control of MAPKs results in varied cellular responses.
The induction of DUSP expression and activity correlates with high MAPK activity to
control the sustained or late phase of MAPK activity that is crucial for inducing IEGs and
forming transcription factor complexes. Red arrows indicate positive regulation
and green arrows indicate negative regulation in the tight regulation loops between
MAPKs and DUSPs. CBP, CREB-binding protein (also known as CREBBP); MAP2K,
MAPK kinase; MAP3K, MAP2K kinase; NFAT, nuclear factor of activated T cells.
398 | MAY 2007 | VOLUME 6
© 2007 Nature Publishing Group
PTP superfamily (106)
An animal model of brain
inflammation. It is mostly used
with rodents and is a model
for the human disease multiple
sclerosis. It is induced with
Dusp2–/– mice were protected in the KxB/N model of
inflammatory arthritis, which is dependent on mast cell
and macrophage activation31.
Drug development — prospects and challenges
There is already considerable evidence that pharma-
cological inhibition of the MAPKs themselves can
modify inflammatory responses in both animal models
and in humans (see the Phase II clinical trials listed in
Supplementary information S1). However, the broad
expression profiles of MAPKs, as well as complex cross-
talk and feedback loops, raise concerns over the poten-
tial side effects of MAPK inhibitors. Indeed, despite the
enthusiasm by various companies to develop MAPK
inhibitors, few have progressed to late-stage clinical
trials, with many producing hepatotoxicity problems
(Supplementary information S1).
Interference of DUSP activity may be an alternative
strategy for manipulating MAPK pathways and immune
responses in a cell-type-specific manner. Controlling
DUSP activity provides opportunities for subduing
immune responses in the case of chronic inflammation
or autoimmunity, or boosting immune responses to fight
cancers or infection. Until the mid-1990s, small-molecule
inhibitors of this class of protein were limited to the
broad-spectrum PTP inhibitor orthovanadate.
Recently, specific inhibitors of DUSP1, DUSP6 and
DUSP22 have been identified (TABLE 1). The differences
in the primary amino-acid sequence within the catalytic
domain of the different subclasses of the 106 protein
tyrosine phosphatases suggest that selective inhibitors
might be achievable. Moreover, the X-ray crystallo-
graphic structures for DUSP2, DUSP6 and DUSP3,
compared with the structures of PTEN (phosphatase and
tensin homologue) or PTP1B (also known as PTPN1),
reveal a different architecture within the active sites. The
different widths and depths within the active sites are
thought to contribute to the differential specificity for
tyrosine, tyrosine/threonine or serine/threonine phos-
phates by the different phosphatases. Thus, the shorter
serine/threonine residues may not gain access to the
deeper binding pocket of the PTP and therefore may be
spared from hydrolysis113.
The active sites of PTPs are ~9 Å (REF. 114), whereas
those of the DUSPs tend to be shallower at ~6 Å
(REFS 89,115). The shallow pocket of VHR-like DUSPs
allows both phosphotyrosine and the shorter phospho-
serine/threonine substrates to reach the catalytic cysteine
at the bottom, whereas the deeper PTP1B pocket permits
only phosphotyrosine access. The wider opening of the
PTEN pocket is consistent with its ability to dephos-
phorylate phosphoinositide lipids and phosphoserine/
Figure 3 | Phosphatases that regulate MAPKs. Of the 159 phosphatases identified in the human genome that operate
in signal transduction, 106 of these are considered to be protein tyrosine phosphatases (PTPs). This PTP superfamily is
further subdivided into 7 categories that are based on structural homology and substrate preference. These categories
are: protein tyrosine phosphatase (PTPs), dual-specificity phosphatases (DUSPs), myotuberlarin-related phosphatases
(MTMs), CDC25 phosphatases, low molecular weight (LMW) phosphatases, inositol-4-phosphatases (Inos.4P) and SAC1-
domain phosphatases55,143. PTPs and some serine/threonine phosphatases (PPs) show activity towards mitogen-activated
protein kinases (MAPKs) by dephosphorylating single tyrosine or threonine residues. Class I DUSPs have activity towards
MAPKs by dephosphorylating both tyrosine and threonine residues and are further subclassified into CH2-motif
containing MAPK phosphatases (MKPs), JSP1-like phosphatases, MKP6-like, VHR-like, slingshot-like and SKPR1/ hyVH1.
PPM, protein phosphatases, magnesium dependent; PPP, phosphoprotein phosphatases.
NATURE REVIEWS | DRUG DISCOVERY
VOLUME 6 | MAY 2007 | 399
© 2007 Nature Publishing Group
threonine substrates in addition to phosphotyrosine116.
Therefore, it seems feasible that compounds disrupt-
ing the catalytic region will display some specificity,
at least between these two main classes. It is also poss-
ible that inhibitors may find an application, even if
they do not show selectivity for individual DUSPs.
Nevertheless, the shallow and hydrophilic nature of the
catalytic domain of DUSPs presents challenges for drug
Targeting protein–protein interactions through
the KIM of DUSPs may be an alternative strategy for
manipulating their activity. A high degree of substrate
specificity between a specific DUSP and MAPK is medi-
ated by the KIM, which serves as a ‘docking site’. KIMs
are defined as short sequence motifs that lie distal to the
phosphoacceptor in the linear amino-acid sequence and
ensure the efficiency and specificity of substrate phos-
phorylation117. Various types of docking sites have been
identified in several MAPK interacting proteins, including
upstream kinases (for example, MEKs), phosphatases
(DUSPs), scaffold proteins, downstream effectors (for
example, MAPKAPKs) and transcription factors, and
these docking sites contribute to the affinity of these
molecules for specific MAPK members118,119. The KIM
domains of multiple DUSPs have been identified, and,
owing to the specificity of the protein–protein inter-
actions at this site, disruption of KIM–MAPK interactions
using small-molecule inhibitors is an intriguing area for
drug discovery. For many PTPs, physical interaction
via the KIM domain of the phosphatase and the target
protein is required for conformational changes in the
phosphatase to significantly increase enzymatic activity,
which otherwise exhibits very low phosphatase activity in
the absence of substrates115,120. This mechanism appears
to be generalized across the DUSPs, but has been most
studied with DUSP6 (REF. 44).
For example, ERK2 binding to DUSP6 via the conserved
XXRRXXKXXLXV in the N-terminal kinase binding
domain95 stabilizes the active conformation of the active
site cysteine115 and results in an approximately 100-fold
increase in enzymatic activity44,87,99. Interestingly, DUSP6
seems to first dephosphorylate the phosphothreonine
residue within the dually phosphorylated TXY motif
on ERK2, dissociate, and subsequently reassociate
with monophosphorylated ERK2 phoshotyrosine120.
Importantly, DUSP6 has been found to engage in
intramolecular dephosphorylation of ERK with a bind-
ing stoichiometry of 1:1; thus ERK-binding-dependent
increases in DUSP6 activity result in the dephosphory-
lation of the same bound ERK molecule, and not a freely
soluble secondary ERK molecule. These considerations
have important implications for the negative regulation
of ERK, given that active ERK1 and ERK2 form dimers
in solution, which may be resistant to inactivation by
DUSP6. Active ERK1 and ERK2 dimers translocate into
the nucleus, and ERK inactivation may be driven by
dimer dissociation and subsequent binding to DUSPs.
Disruption of this process by chemical inhibition of
this positively charged site is therefore a viable although
unproven strategy to control MAPK activation.
It is challenging to design and develop small-molecule
inhibitors that exclusively target the catalytic domain of
Table 2 | A summary of the expression patterns of DUSPs in immune cell types and tissues*
Mast cells (IgE stimulated)
Neutrophils (IL-8 or
DCs (LPS stimulated)
Naive B cells
Memory B cells
Memory B cells (IgM)
*Determined through transcript expression profiling31,73,79 and Gene Expression Omnibus database sets GSE3526 and GSE3982.
DC, dendritic cell; DUSP, dual-specificity phosphatases; IL, interleukin; LPS, lipopolysaccharide; NK, natural killer; TH, T helper.
DUSP1, 2, 3, 4, 8, 9, 14, 18, 26
DUSP1, 3, 5, 7, 8, 9, 16, 18, 22
DUSP3, 4, 7, 12, 14
DUSP5, 7, 12, 16, 22
DUSP5, 7, 8, 9, 10, 16, 18, 22, 26
DUSP4, 10, 14
DUSP1, 2, 6
DUSP1, 3, 6, 7, 8, 9, 12, 16, 18, 26
DUSP1, 6, 8, 10, 26
DUSP2, 5, 7, 10, 14, 22
DUSP2, 3, 4, 7, 9, 12, 14, 16, 18
DUSP1, 2, 16
DUSP3, 4, 14, 16, 18
DUSP3, 4, 6, 7, 10, 14, 16, 22
DUSP3, 4, 7, 14, 16, 18
DUSP3, 4, 6, 7, 8, 9, 10, 14, 16, 18, 26
DUSP1, 3, 6, 8, 9, 18, 22, 26
DUSP1, 3, 8, 9, 18, 22, 26
DUSP3, 5, 7, 8, 9, 14, 18, 22, 26
DUSP4, 5, 6, 10, 12, 14, 22
DUSP3, 4, 8, 9, 10, 14, 16, 26
DUSP3, 7, 8, 9, 10, 14, 26
DUSP3, 8, 13, 18, 22, 26
DUSP3, 4, 7, 8, 9, 14, 26
DUSP6, 7, 8, 9, 10, 22, 26
DUSP7, 8, 9, 12, 18, 26
DUSP5, 6, 8, 9, 10, 22, 26
DUSP 5, 12, 22
DUSP2, 7, 10, 12, 14, 16
DUSP2, 5, 6, 7, 10, 12, 14, 16
DUSP1, 2, 6, 10, 12, 16
DUSP2, 3, 7, 8, 9, 16, 18, 26
DUSP1, 5, 7, 11, 22
DUSP1, 4, 5, 11, 16, 22
DUSP1, 4, 7, 12, 16
DUSP1, 6, 10, 11, 16, 22
DUSP1, 2, 5, 12
DUSP1, 2, 5
DUSP1, 2, 12
DUSP2, 5, 6, 10
400 | MAY 2007 | VOLUME 6
© 2007 Nature Publishing Group
proteins. This is due mostly to the fact that they must
mimic a phosphate moiety, which will result in the mol-
ecule being highly negatively charged and so lacking drug-
like properties121. Producing ATP mimetics seems to make
targeting kinases easier. Nevertheless there are shortcom-
ings to this approach, mainly because of a lack of specifi-
city that is due to the conservation of the ATP-binding
pockets among the many kinases122.
Cyclosporin, a calcineurin phosphatase inhibitor,
does not directly block protein–protein interactions, but
rather facilitates ternary complex formation between
cyclophilin A and calcineurin to affect calcineurin func-
tion. Therefore, other approaches exist for targets that
are difficult to ‘drug’ through conventional small-
molecule inhibition. Infinity Pharmaceutical’s success-
ful blocker of BCL-2 activity disrupts protein interaction
rather than protein activity itself. As DUSPs become
more attractive for drug development, owing to their
central role in MAPK regulation, additional efforts
will follow to effectively target these molecules. Other
approaches that could be used for DUSP inhibition
include RNA interference or anti-sense approaches as
used clinically by Isis Pharmaceuticals for the phos-
DUSPs, a subclass of the PTPs, are emerging as attrac-
tive targets for drug discovery. DUSP inhibitors might
be used to manipulate MAPK and cellular responses
in both positive and negative ways. However the role
of DUSPs in various cells and biological processes still
needs to be determined. Further validation will come
from DUSP knockout studies, as well as inducible or
tissue-selective mutations of certain DUSP family mem-
bers. Understanding the physiological roles of the many
DUSPs should pave the way for developing new immuno-
modulatory therapies for inflammation or cancer, and
for further understanding MAPK signalling in physio-
logical responses. Therefore, inhibition or activation of
some of these phosphatases offers an attractive means
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The authors would like to thank T. Brummer and R. Hooft van
Huijsduijnen for critical evaluation of the manuscript, and
S. Tange and K. Good for B-cell microarray data.
Competing interests statement
The authors declare no competing financial interests.
The following terms in this article are linked online to:
DUSP1 | DUSP2 | DUSP3 | DUSP4 | DUSP5 | DUSP6 | DUSP7 |
DUSP8 | DUSP9 | DUSP10 | DUSP16 | DUSP22 | MAP3K8 |
MAPK8 | MAPK9 | MAPK14
Garvan Institute: http://www.garvan.org.au
Gene Expression Omnibus database:
Merck Serono: http://www.merckserono.net
Protein Tyrosine Phosphatases web site: http://ptp.cshl.edu
See online article: S1 (table)
Access to this links box is available online.
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