| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Serono Pharmaceutical Research Institute, Ares-Serono International SA, 1228 Plan-les-Ouates, Geneva, Switzerland
1Correspondence: Serono Pharmaceutical Research Institute, Ares-Serono International SA, 1228 Plan-les-Ouates, Geneva, Switzerland. E mail. steve.arkinstall@serono.com
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
Key Words: MAP kinases • protein phosphatases • dual • specificity phosphatases • signal transduction
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. A similar
proportion of genes are also committed to direct control of protein
phosphorylation in the budding yeast Saccharomyces
cerevisiae (1.9% of all genes are protein kinases and 0.23% are
PTPs) (2)
. Extrapolation from these organisms predicts
that the human genome may encode 2000 protein kinases and up to 500
PTPs, providing a complex diversity of enzymes for controlling protein
phosphorylation and orchestrating essential changes in cell function. |
MAMMALIAN MITOGEN-ACTIVATED PROTEIN KINASES |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
4
5
6)
. These display a high
level of evolutionary conservation and are essential for many cell
functions throughout the animal kingdom. These include mating in yeast,
morphogenesis in slime mold, vulval development in worms, eye
development in flies, mesoderm induction in frogs, as well as
lymphocyte differentiation and neuronal death in mammals (5
, 7
8
9
10)
. Extracellular signal-regulated kinase-1 (ERK1) and ERK2,
also known as p44 and p42 MAP kinases, represent the prototypical MAP
kinases in mammalian cells. ERK MAP kinase catalytic activation
requires phosphorylation by an upstream dual specificity MAP kinase/ERK
kinase (MEK) exemplified by MEK-1, which in turn is phosphorylated and
activated by a MAP kinase kinase kinase of the Raf family. Of these,
c-Raf-1 has been studied extensively and found to undergo activation at
the plasma membrane after binding to the GTP-bound form of the low
molecular weight G-protein p21ras (3
4
5
6)
. In all, four
mammalian MAP kinase cascades are currently recognized that, in
addition to ERK, include c-Jun NH2-terminal
kinase/stress-activated protein kinase (JNK/SAPK), p38/RK/CSBP (p38),
and big mitogen-activated protein kinase-1/ERK5 (BMK-1/ERK5) pathways
(3
4
5
6
, 11)
. As with ERK, these MAP kinases are activated
by phosphorylation that occurs at a specific threonine and tyrosine
residue localized within the activation loop motif TxY of
kinase subdomain VIII (where x represents glutamate in ERK,
proline in JNK/SAPK, and glycine in p38 MAP kinases). Multiple genes
and splice variants for each MAP kinase as well as a number of specific
upstream activating kinases responsible for MAP kinase phosphorylation
and activation have been identified; these are illustrated in
Fig. 1
.
|
Different cell stimuli activate preferentially distinct MAP kinases.
Hence, many growth factor and G-protein linked receptors, cell
adhesion, phorbol esters, and some oncogenes are linked to activation
of the ERKs, whereas inflammatory cytokines, trophic factor
deprivation, and a number of cell stresses lead preferentially to
activation of JNK/SAPK and p38 MAP kinases (3
4
5
6)
. Less is
known about BMK-1/ERK5 responsiveness, although this MAP kinase has
been reported to respond to both growth factors and stressful stimuli
(11)
(Fig. 1)
. MAP kinases target several substrate
proteins for phosphorylation, including additional ‘downstream’
serine/threonine kinases (which themselves become activated),
cytoskeletal elements, regulators of cell death, as well as a number of
nuclear receptors and transcription factors (Fig. 1)
. Such an array of
substrates suggests a key role for MAP kinases in controlling diverse
cell functions; recent studies using chemical inhibitors and dominant
inhibitory or active mutant kinases, as well as analysis of mice after
gene deletion, support this. For example, ERK MAP kinases are involved
in cellular chemotaxis, cell cycle progression and mitogenesis,
oncogenic transformation and metastasis, neuronal differentiation and
survival, and in processes underlying memory and learning (3
4
5
6
, 12
13
14
15
16
17
18
19)
. One recent study suggests that BMK-1/ERK5 can also
participate in pathways leading to cell cycle progression and
proliferation (11)
. Conversely, JNK/SAPK and p38 MAP
kinases are important in pathways controlling T cell differentiation,
production of inflammatory cytokines and eicosanoids, and apoptotic
cell death (3
, 8
9
10
, 19
20
21
22
23
24)
. These observations indicate
that mechanisms controlling MAP kinases activation state are of
critical importance to several diverse aspects of normal and
pathological cell functions. In this regard, studies over recent years
have provided clear evidence for important and specific roles for
upstream kinases in phosphorylating and activating MAP kinases in
response to extracellular stimuli (3
4
5
6)
(Fig. 1)
. In
addition to stimulatory input from such MAP kinase kinases, however,
activation of MAP kinase is a reversible process even in the continued
presence of activating stimuli, indicating that protein phosphatases
are also likely to provide an important mechanism for control.
|
MAP KINASE INACTIVATION BY THREONINE OR TYROSINE DEPHOSPHORYLATION |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. It is believed that different temporal patterns of
ERK MAP kinase activation elicited by EGF and NGF underlie their
differential effects to drive either cellular proliferation or
differentiation, respectively (6)
. Using PC12 cells as a
model system to identify key phosphatases suppressing ERK activation,
biochemical studies revealed that early rapid inactivation of these MAP
kinases reflects, in part, threonine dephosphorylation by the PPP
serine/threonine protein phosphatase PP2A (25)
(Fig. 2
). In addition to threonine dephosphorylation, these studies also
indicated that tyrosine-specific protein phosphatases (PTPs) also
contribute to ERK MAP kinase inactivation (25)
. Currently,
50 or more PTPs have been characterized (26
27
28)
, and
although the PC12 cell PTPs were not identified molecularly
(25)
, recent studies in other cell types have identified a
possible role for three related PTP gene family members. Hence, PTP-SL
(also known as PCPTP1) and STEP are two homologous neuronal PTPs
existing in both transmembrane and cytosolic forms that bind tightly as
well as dephosphorylate and inactivate ERKs (29)
. HePTP
(same as LC-PTP) is an additional cytosolic PTP present in lymphoid
tissue also reported recently to bind and inactivate this class of MAP
kinase (30)
(Fig. 2)
. PTP-SL, STEP, and HePTP appear to
act as functional homologues of the tyrosine-specific PTPs Ptp2 and
Ptp3 as well as Pyp1 and Pyp2, identified genetically as
down-regulators of MAP kinases in budding and fission yeast,
respectively (31
32
33
34)
.
|
Notwithstanding the importance of these early reports on PP2A and tyrosine-specific PTPs inactivating ERKs, little is known of their general importance in terminating MAP kinase signaling, of the molecular mechanisms that may control their phosphatase catalytic activity, or of their specificity for inactivating different MAP kinase isoforms. In contrast to these protein phosphatase classes, there has been significant and rapid progress in our understanding of the role played by a subclass of PTP that possess activity for dephosphorylating both phosphotyrosine and phosphothreonine residues, hereafter termed dual specificity phosphatases (DSPs). It is our current understanding of MAP kinase control by DSPs that is the focus of this review.
|
THE DSP FAMILY |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. In 1992, the first mammalian DSP was identified as
the mouse immediate early gene 3CH134 (later also cloned as Erp) or its
human orthologue CL100, which is induced rapidly after exposure to
growth factors, heat shock, or oxidative stress (36
37
38)
.
Sequence homology with VH1 suggested that CL100/3CH134 was a tyrosine
phosphatase and this was confirmed after its expression in bacteria.
Recombinant CL100/3CH134 was also shown to dephosphorylate threonine
and tyrosine residues of ERK MAP kinases, and this was paralleled by
kinase inactivation. These studies showed that CL100/3CH134 was
specific for dephosphorylation of ERK MAP kinases when compared to a
number of other unrelated phosphoproteins (36
, 39
40
41)
. In
mammalian cells, a correlation between 3CH134 levels and ERK
inactivation suggested specificity for inactivation of MAP kinases,
leading to its renaming as MAP kinase phosphatase-1 (MKP-1)
(42)
.
Despite this important early work, it is now unclear whether
CL100/MKP-1 is a physiological regulator of the ERKs rather than other
subclasses of MAP kinase. First, we now recognize that MKP-1 is at
least as effective in inactivating JNK/SAPK and p38 when compared to
ERK MAP kinases (43
, 44)
. Second, ERK activity is
apparently normal after deletion of the CL100/MKP-1 gene in mice
(45)
. Third, newly identified members of the DSP gene
family appear highly selective for ERK and may represent the true
physiological regulators of this MAP kinase isoform (see below).
Since the initial cloning of CL100/MKP-1, eight additional mammalian
DSP gene family members have been identified and characterized. These
include PAC1 (46
, 47)
, hVH-2/MKP-2 (also cloned as TYP-1)
(48
49
50)
, hVH3/B23 (51
, 52)
, hVH-5 (human
orthologue of M3/6) (53
, 54)
, MKP-3/PYST1 (same as rVH6)
(55
56
57)
, B59 (full-length clone of PYST2 and human
orthologue of MKP-X) (56
57
58)
, MKP-4 (59)
,
and MKP-5 (60)
(Fig. 3
). These DSPs all appear to be effective in mediating inactivation of
MAP kinases. VHR is an additional mammalian homologue of VH1
(61)
, but it lacks an amino-terminal extension identified
in all other DSP gene products that is now known to be important for
targeting specific MAP kinase substrates (see below). VHR also
dephosphorylates growth factor receptor tyrosine kinases and
appears to be relatively inactivate against MAP kinases (58
, 61)
. For these reasons, we consider VHR to represent a distinct
DSP subclass and so it is not considered further here.
|
|
WHERE ARE DSPs EXPRESSED? |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
, 47
, 53
, 54
, 59
, 60)
(Table 1
). Other DSPs also reveal a restricted expression pattern when studied
by in situ analysis. For instance, although Northern
blotting reveals that CL100/MKP-1, B29 (MKP-X), MKP-3/PYST1, and
hVH-3/B23 are all present in adult rat brain, more detailed analysis in
brain slices demonstrates a highly localized and distinct expression
pattern for these DSP gene family members (62)
. In
addition, DSPs can also occupy distinct subcellular compartments.
Hence, whereas CL100/MKP-1, PAC-1, hVH-2/MKP-2, and hVH-3/B23 are all
localized within the nucleus, MKP-3/PYST1 appears to be exclusively
cytosolic (46
, 48
, 51
, 56
, 57)
. MKP-4, in contrast, is
present in cytosol as well as in punctate nuclear bodies colocalizing
with the promyelocytic protein (59)
. Other DSPs are
different, again as illustrated by M3/6, which may be either nuclear or
cytosolic depending on its cellular environment (54)
.
|
|
TRANSCRIPTIONAL CONTROL OF DSPs |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
, 37)
. Other DSP genes
also undergo transcriptional up-regulation in cell lines exposed to
growth factors and/or cellular stress (summarized in Table 1
). In some
instances, DSP gene induction appears specific for a given stimulus. In
PC12 cells, for instance, CL100/MKP-1, hVH-2/MKP-2, and hVH-5 all
undergo rapid induction as immediate early genes in response to
mitogenic factors whereas MKP-3/PYST1 expression is stimulated
exclusively by agents promoting neuronal differentiation, most
particularly by NGF (50
, 53
, 54
, 56
, 63)
. Tight
transcriptional control of DSP genes also occurs in vivo as
indicated by studies in rats undergoing kainic acid-induced seizure
activity where CL100/MKP-1, hVH-3/B23, PAC-1, and MKP-3/PYST1 are all
reversibly up-regulated in discrete brain regions. Under these
conditions of up-regulation, different DSPs map to distinct brain areas
displaying either neuronal plasticity, apoptotic death, or survival
(62
, 64)
. CL100/MKP-1 also displays transient and highly
regionalized induction within specific brain regions during normal
embryonic development (62)
. Mechanisms controlling DSP
induction are likely to be complex although expression of some gene
family members, including CL100/MKP-1, hVH-2/MKP-2, and PAC1, is
reported to be dependent at least in part on MAP kinase activation
(65
66
67)
. This provides clear scope for negative feedback
of the inducing MAP kinase or for regulatory cross talk between
parallel MAP kinase pathways. |
CHROMOSOMAL LOCALIZATION OF DSP GENES |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
15
16
, 68
, 69)
. Consistent with this, expression of CL100/MKP-1, hVH-3/B23,
or B59 inhibits oncogene-driven DNA synthesis and cell transformation
(58
, 70)
. With such a potential tumor suppressor role in
mind, it is of note that the chromosomal localization of all human DSP
genes have now been mapped and several of these occupy regions
implicated in genetic reorganizations associated with the incidence of
some cancers (38
, 54
, 59
, 71
, 72)
(Table 1)
. MKP-3/PYST1,
for instance, is localized to a region of frequent allelic loss in
pancreatic cancer (12q21–23) and also displays lower levels of
expression in several pancreatic tumor cell lines (73)
. |
DSP CATALYTIC DOMAIN |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
). Screening the EST database reveals at least six
additional potential mammalian members of this gene family
displaying a conserved DSP catalytic active site (Fig. 3B
).
This motif contains at least two residues (underlined) known to be
critically important within a two-step catalytic reaction. According to
a model of catalysis by PTPs, an essential cysteine functions as an
active site nucleophile forming a covalent thio-phosphate intermediate,
whereas the aspartate acts as a general acid to donate a proton to the
leaving group. The same aspartate then probably acts as a general base
taking a proton from a water molecule, which then attacks the
phospho-enzyme intermediate to eliminate phosphate and regenerate
active enzyme (28)
(Fig. 3C
). Both threonine
and tyrosine residues are likely to be dephosphorylated by the same
catalytic mechanism, and the crystal structure of VHR suggests that a
shallow active site (as opposed to the deeper cleft of
tyrosine-specific PTPs) accounts for the less stringent phosphoamino
acid specificity of the DSPs (28)
.
|
|
NATURALLY OCCURRING INACTIVE DSP ‘MUTANTS’ |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. This indicates that STYX could be the prototype of a
new subfamily of catalytically inactive DSPs, though their functional
significance is currently unclear. |
SEQUENCE DIVERGENCE WITHIN THE AMINO-TERMINAL OF DSPs |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. One role of specific
sequences within the amino terminus region could be to define their
subcellular localization. Indeed, a potential nuclear localization
motif has been suggested within the amino terminus of hVH-3/B23
(52)
, and similar sequences can also be identified in
CL100/MKP-1, hVH-2/MKP-2, and PAC-1. In contrast, putative nuclear
export motifs have been proposed within the amino terminus of rVH-6
(MKP-3/PYST1) and B59 (55
, 58)
. The presence of these
motifs is consistent with the subcellular localization reported for
these DSPs (see above). Despite sequence divergence within the
amino-terminal, all DSPs possess two short stretches of homology
containing residues conserved with two segments flanking the active
site of the Cdc25 phosphatase. These motifs have been designated CH2
(Cdc25 homology regions) A and B or, alternatively, CH2-N and CH2-C
(75
, 76)
. The functional significance of these motifs is
currently unknown, although a role for the amino-terminal in binding
substrate MAP kinases (see below) could reflect properties associated
with one or both CH2 domains. Examination of the gene structures of
CL100/MKP-1 and PAC1 (38
, 76
, 77)
indicates that their
amino termini may have distinct evolutionary origins to the
carboxyl-terminal catalytic core. In fact, of four exons comprising the
murine CL100/MKP-1 gene, exons 1 and 2 encompass the CH2-N and CH2-C
domains, respectively, tempting speculation that these exons may have
converged with a smaller gene encoding simply a DSP catalytic core. |
SELECTIVE MAP KINASE INACTIVATION BY DSPs |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
, 78)
. This contrasts
with another DSP, M3/6, which appears highly specific for inactivating
JNK/SAPK and p38 MAP kinases, as even high expression levels failed to
inhibit ERK activation by growth factor or oncogenic p21ras
(78)
. Other DSPs also display selectivity in that MKP-4 is
more effective at inactivating ERKs and MKP-1 acts preferentially on
JNK/SAPK and p38 MAP kinases, whereas PAC-1 and hVH-2/MKP-2 show
limited specificity for ERK and either p38 and JNK/SAPK, respectively
(43
, 44
, 59)
(Table 1)
. Although this selectivity could
reflect merely a substrate preference by the catalytic domains of these
different DSPs, it appears that an additional unexpected mechanism
accounts at least in part for specific MAP kinase inactivation. |
MAP KINASE SELECTIVITY REFLECTS DSP BINDING AND CATALYTIC ACTIVATION |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
. More detailed analysis of this interaction soon
revealed that MKP-3/PYST1 binding to ERK MAP kinases was direct and
unexpectedly involved the noncatalytic amino terminus of the
MKP-3/PYST1 protein. Indeed, when expressed alone, the
carboxyl-terminal catalytic domain of MKP-3/PYST1 was devoid of ERK
binding activity (79)
. Strikingly, when interaction with
different MAP kinases was compared, the MKP-3/PYST1 amino terminus was
found to bind tightly to both ERK1 and ERK2 but not to JNK3 (SAPKß),
JNK2 (SAPK
), or p38 MAP kinases (79
, 80)
. This binding
specificity mirrors the selectivity of MKP-3/PYST1 for inactivating
different MAP kinases and raised the question of whether amino-terminal
substrate binding alters the catalytic activity of this DSP. As
indicated by MKP-3/PYST1-dependent hydrolysis of the artificial
substrate p-nitrophenyl phosphate (p-NPP),
purified ERK2 was found to stimulate the catalytic activity of this DSP
by more than 40-fold. This effect was independent of protein kinase
activity and required binding of ERK2 to the noncatalytic amino
terminus of MKP-3/PYST1. Neither JNK/SAPK nor p38 MAP kinases bound or
stimulated significant MKP-3/PYST1 catalytic activity over basal levels
(80)
. Together, these observations indicate that
MKP-3/PYST1 selectivity for ERK MAP kinases may reflect tight substrate
binding through its amino terminus, leading to its catalytic activation
and consequent dephosphorylation and inactivation of the bound MAP
kinase (Fig. 5
). In support of this, an amino-terminally truncated version of
MKP-3/PYST1 devoid of binding activity loses its selectivity for
inactivating ERKs and displays similar but reduced activity against all
MAP kinases (79
, 80)
. In addition, a mutant form of ERK2
(D319N) analogous to the Drosophila gain-of-function ERK-A
mutation sevenmaker is disabled in its ability to either
bind or activate MKP-3/PYST1. This may account for its hypersensitivity
to activation in vivo as well as its resistance to
inactivation by DSPs (43
, 80
, 81)
. Purified MKP-4
(80)
and MKP-1 (S. Arkinstall, unpublished observations)
also bind and undergo catalytic activation by purified MAP kinases in
parallel with their enzymatic selectivity, suggesting that this is a
general mechanism for activating DSPs and targeted inactivation of MAP
kinases.
|
|
MODEL FOR MAP KINASE CONTROL BY DSPs |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
). Stimulation by growth factors, cytokines, cell stresses, or some
active oncogenes leads to rapid transcription of one or a subset of DSP
genes. Increased DSP transcription may reflect activation of specific
MAP kinases, although alternative pathways are not excluded. After
translation of the DSP mRNA into protein, the catalytically inactive
DSP translocates to a specific subcellular compartment within either
the nucleus or cytosol. Upon encountering its target MAP kinase, the
DSP binds tightly through its amino terminus, which in turn triggers
activation of the phosphatase catalytic domain. If the bound MAP kinase
is already activated, then this will result in its rapid inactivation.
Conversely, if the MAP kinase is not active, then its tight interaction
with an active DSP is expected to block any possibility of kinase
activation by a subsequent stimulus. MAP kinases that fail to bind the
DSP within its amino terminus remain active or susceptible to
activation after extracellular stimulation. Depending on their cellular
localization, these regulatory effects allow for selected inhibition of
MAP kinase activities in specific subcellular compartments. Some DSPs
have been shown to possess short half-lives (38
, 39)
,
suggesting that in the absence of continued gene transcription and
protein synthesis, their rapid turnover limits their duration of action
in cells. Overall, tight control of DSP gene induction, combined with
their differential binding and catalytic activation by a specific
repertoire of MAP kinases, provides a sophisticated mechanism for rapid
and targeted inactivation of selected MAP kinase activities.
|
From a broader perspective, tight binding between DSP family members
and MAP kinases represents a further example of an association
indicative of higher order complexes within cellular signal
transduction pathways. ERK, for example, binds to a number of proteins
involved in this MAP kinase cascade. These include the activating
kinase MEK-1, the target transcription factors Elk-1, c-Myc and
STAT1, downstream kinases including the MAPKAP-K1 (p90 S6 kinase,
RSK), Mnk1, and Mnk2, as well as the potential scaffold proteins MP1
and Ksr (82
83
84
85
86
87
88
89
90)
. Together with the DSP MKP-3/PYST1, these
proteins may form stable or dynamic multimolecular complexes similar to
those underlying pheromone-stimulated MAP kinase activation in budding
yeast (7)
. Ordered protein complexes probably play a major
role defining specificity of communication within MAP kinase signaling
cascades and is an emerging theme also seen in other signal
transduction pathways, as exemplified in the multimeric ‘signalsome’
comprising several essential components required for activation of the
transcription factor NF-
B (91)
.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMAMMALIAN MITOGEN-ACTIVATED...MAP KINASE INACTIVATION BY...THE DSP FAMILYWHERE ARE DSPs EXPRESSED?TRANSCRIPTIONAL CONTROL OF DSPsCHROMOSOMAL LOCALIZATION OF DSP...DSP CATALYTIC DOMAINNATURALLY OCCURRING INACTIVE DSP...SEQUENCE DIVERGENCE WITHIN THE...SELECTIVE MAP KINASE...MAP KINASE SELECTIVITY REFLECTS...MODEL FOR MAP KINASE...REFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  A. Jurek, K. Amagasaki, A. Gembarska, C.-H. Heldin, and J. Lennartsson Negative and Positive Regulation of MAPK Phosphatase 3 Controls Platelet-derived Growth Factor-induced Erk Activation J. Biol. Chem., February 13, 2009; 284(7): 4626 - 4634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Kinney, U. M. Chandrasekharan, L. Yang, J. Shen, M. Kinter, M. S. McDermott, and P. E. DiCorleto Histone H3 as a novel substrate for MAP kinase phosphatase-1 Am J Physiol Cell Physiol, February 1, 2009; 296(2): C242 - C249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pages MAP kinase phosphatase-1: a link between cell signaling and histone phosphorylation. Focus on "Histone H3 as a novel substrate for MAP kinase phosphatase-1" Am J Physiol Cell Physiol, February 1, 2009; 296(2): C233 - C234. [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Cho and S. G. Kim A Novel Mitogen-Activated Protein Kinase Phosphatase-1 and Glucocorticoid Receptor (GR) Interacting Protein-1-Dependent Combinatorial Mechanism of Gene Transrepression by GR Mol. Endocrinol., January 1, 2009; 23(1): 86 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Evans and G. N. Somero A microarray-based transcriptomic time-course of hyper- and hypo-osmotic stress signaling events in the euryhaline fish Gillichthys mirabilis: osmosensors to effectors J. Exp. Biol., November 15, 2008; 211(22): 3636 - 3649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Maillet, N. H. Purcell, M. A. Sargent, A. J. York, O. F. Bueno, and J. D. Molkentin DUSP6 (MKP3) Null Mice Show Enhanced ERK1/2 Phosphorylation at Baseline and Increased Myocyte Proliferation in the Heart Affecting Disease Susceptibility J. Biol. Chem., November 7, 2008; 283(45): 31246 - 31255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Valledor, L. Arpa, E. Sanchez-Tillo, M. Comalada, C. Casals, J. Xaus, C. Caelles, J. Lloberas, and A. Celada IFN-{gamma}-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation Blood, October 15, 2008; 112(8): 3274 - 3282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Johansson-Haque, E. Palanichamy, and S. Okret Stimulation of MAPK-phosphatase 1 gene expression by glucocorticoids occurs through a tethering mechanism involving C/EBP J. Mol. Endocrinol., October 1, 2008; 41(4): 239 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wang, Y. Song, D.-B. Chen, and J. Zheng Protein Phosphatase 3 Differentially Modulates Vascular Endothelial Growth Factor- and Fibroblast Growth Factor 2-Stimulated Cell Proliferation and Signaling in Ovine Fetoplacental Artery Endothelial Cells Biol Reprod, October 1, 2008; 79(4): 704 - 710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Bouhidel, S. Pons, R. Souktani, R. Zini, A. Berdeaux, and B. Ghaleh Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1580 - H1586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-Y. Zhang, Z.-Q. Mei, J.-W. Wu, and Z.-X. Wang Enzymatic Activity and Substrate Specificity of Mitogen-activated Protein Kinase p38{alpha} in Different Phosphorylation States J. Biol. Chem., September 26, 2008; 283(39): 26591 - 26601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Chan, V. W.S. Liu, G. S.W. Tsao, K.-M. Yao, T. Furukawa, K. K.L. Chan, and H. Y.S. Ngan Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells Carcinogenesis, September 1, 2008; 29(9): 1742 - 1750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tchivilev, N. R. Madamanchi, A. E. Vendrov, X.-L. Niu, and M. S. Runge Identification of a Protective Role for Protein Phosphatase 1c{gamma}1 against Oxidative Stress-induced Vascular Smooth Muscle Cell Apoptosis J. Biol. Chem., August 8, 2008; 283(32): 22193 - 22205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shi, J. M. Scheffler, J. M. Pleitner, C. Zeng, S. Park, K. M. Hannon, A. L. Grant, and D. E. Gerrard Modulation of skeletal muscle fiber type by mitogen-activated protein kinase signaling FASEB J, August 1, 2008; 22(8): 2990 - 3000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, N. Cao, D. Nantajit, M. Fan, Y. Liu, and J. J. Li Mitogen-activated Protein Kinase Phosphatase-1 Represses c-Jun NH2-terminal Kinase-mediated Apoptosis via NF-{kappa}B Regulation J. Biol. Chem., July 25, 2008; 283(30): 21011 - 21023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Tephly and A. B. Carter Asbestos-Induced MKP-3 Expression Augments TNF-{alpha} Gene Expression in Human Monocytes Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 113 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Fan, M. Shimada, Z. Liu, N. Cahill, N. Noma, Y. Wu, J. Gossen, and J. S. Richards Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation Development, June 15, 2008; 135(12): 2127 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Cao, C. Bao, E. Padalko, and C. J. Lowenstein Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling J. Exp. Med., June 9, 2008; 205(6): 1491 - 1503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Przyklenk, M. Maynard, C. E. Darling, and P. Whittaker Aging Mouse Hearts Are Refractory to Infarct Size Reduction With Post-Conditioning J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1393 - 1398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Agarwal, S. K. Burley, and S. Swaminathan Structure of Human Dual Specificity Protein Phosphatase 23, VHZ, Enzyme-Substrate/Product Complex J. Biol. Chem., April 4, 2008; 283(14): 8946 - 8953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Padmos, M. H. J. Hillegers, E. M. Knijff, R. Vonk, A. Bouvy, F. J. T. Staal, D. de Ridder, R. W. Kupka, W. A. Nolen, and H. A. Drexhage A Discriminating Messenger RNA Signature for Bipolar Disorder Formed by an Aberrant Expression of Inflammatory Genes in Monocytes Arch Gen Psychiatry, April 1, 2008; 65(4): 395 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Medhora, A. Dhanasekaran, P. F. Pratt Jr., C. R. Cook, L. K. Dunn, S. K. Gruenloh, and E. R. Jacobs Role of JNK in network formation of human lung microvascular endothelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L676 - L685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Thalhamer, M. A. McGrath, and M. M. Harnett MAPKs and their relevance to arthritis and inflammation Rheumatology, April 1, 2008; 47(4): 409 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kairouz-Wahbe, H. Biliran, X. Luo, I. Khor, M. Wankell, C. Besch-Williford, J. Pascual, R. Oshima, and E. Ruoslahti Anoikis effector Bit1 negatively regulates Erk activity PNAS, February 5, 2008; 105(5): 1528 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Harwood, L. Shu, and P. J. Houghton mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A J. Biol. Chem., February 1, 2008; 283(5): 2575 - 2585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wang, J.-Y. Zhou, and G. S. Wu ERK-Dependent MKP-1 Mediated Cisplatin Resistance in Human Ovarian Cancer Cells Cancer Res., December 15, 2007; 67(24): 11933 - 11941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Horsch, H. de Wet, M. M. Schuurmans, F. Allie-Reid, A. C. B. Cato, J. Cunningham, J. M. Burrin, F. S. Hough, and P. A. Hulley Mitogen-Activated Protein Kinase Phosphatase 1/Dual Specificity Phosphatase 1 Mediates Glucocorticoid Inhibition of Osteoblast Proliferation Mol. Endocrinol., December 1, 2007; 21(12): 2929 - 2940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Morisco, C. Marrone, V. Trimarco, S. Crispo, M. G. Monti, J. Sadoshima, and B. Trimarco Insulin resistance affects the cytoprotective effect of insulin in cardiomyocytes through an impairment of MAPK phosphatase-1 expression Cardiovasc Res, December 1, 2007; 76(3): 453 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Matsushita, T. Gotze, and M. Korc Hepatocyte Growth Factor Mediated Cell Invasion in Pancreatic Cancer Cells Is Dependent on Neuropilin-1 Cancer Res., November 1, 2007; 67(21): 10309 - 10316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. V. Maier, S. Brema, J. Tuckermann, U. Herzer, M. Klein, M. Stassen, A. Moorthy, and A. C. B. Cato Dual Specificity Phosphatase 1 Knockout Mice Show Enhanced Susceptibility to Anaphylaxis but Are Sensitive to Glucocorticoids Mol. Endocrinol., November 1, 2007; 21(11): 2663 - 2671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Teng, W.-N. Huang, and T.-C. Meng Several Dual Specificity Phosphatases Coordinate to Control the Magnitude and Duration of JNK Activation in Signaling Response to Oxidative Stress J. Biol. Chem., September 28, 2007; 282(39): 28395 - 28407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Tephly and A. B. Carter Differential Expression and Oxidation of MKP-1 Modulates TNF-{alpha} Gene Expression Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 366 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Pasini, M. Anselmi, U. Garbin, E. Franchi, C. Stranieri, M.C. Nava, V. Boccioletti, C. Vassanelli, and L. Cominacini Enhanced Levels of Oxidized Low-Density Lipoprotein Prime Monocytes to Cytokine Overproduction via Upregulation of CD14 and Toll-Like Receptor 4 in Unstable Angina Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1991 - 1997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ito, T. Suganami, Y. Miyamoto, Y. Yoshimasa, M. Takeya, Y. Kamei, and Y. Ogawa Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy J. Biol. Chem., August 31, 2007; 282(35): 25445 - 25452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Lee and B. E. Ellis Arabidopsis MAPK Phosphatase 2 (MKP2) Positively Regulates Oxidative Stress Tolerance and Inactivates the MPK3 and MPK6 MAPKs J. Biol. Chem., August 24, 2007; 282(34): 25020 - 25029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Razzaque Cisplatin nephropathy: is cytotoxicity avoidable? Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2112 - 2116. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Issa, S. Xie, N. Khorasani, M. Sukkar, I. M. Adcock, K.-Y. Lee, and K. F. Chung Corticosteroid Inhibition of Growth-Related Oncogene Protein-{alpha} via Mitogen-Activated Kinase Phosphatase-1 in Airway Smooth Muscle Cells J. Immunol., June 1, 2007; 178(11): 7366 - 7375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tu, W. Wu, T. Wu, Z. Cao, R. Wilkins, B.-H. Toh, M. E. Cooper, and Z. Chai Antiproliferative Autoantigen CDA1 Transcriptionally Up-regulates p21Waf1/Cip1 by Activating p53 and MEK/ERK1/2 MAPK Pathways J. Biol. Chem., April 20, 2007; 282(16): 11722 - 11731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Doi, S. Cho, I. Yujnovsky, J. Hirayama, N. Cermakian, A. C. B. Cato, and P. Sassone-Corsi Light-Inducible and Clock-Controlled Expression of MAP Kinase Phosphatase 1 in Mouse Central Pacemaker Neurons J Biol Rhythms, April 1, 2007; 22(2): 127 - 139. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Salojin and T. Oravecz Regulation of innate immunity by MAPK dual-specificity phosphatases: knockout models reveal new tricks of old genes J. Leukoc. Biol., April 1, 2007; 81(4): 860 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Sharma, S. M. Meeran, and S. K. Katiyar Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-{kappa}B signaling in in vivo SKH-1 hairless mice Mol. Cancer Ther., March 1, 2007; 6(3): 995 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Shi, Y.-J. Chiu, Y. Cho, T. A. Bullard, M. Sokabe, and K. Fujiwara Down-regulation of ERK but not MEK phosphorylation in cultured endothelial cells by repeated changes in cyclic stretch Cardiovasc Res, March 1, 2007; 73(4): 813 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tresini, A. Lorenzini, C. Torres, and V. J. Cristofalo Modulation of Replicative Senescence of Diploid Human Cells by Nuclear ERK Signaling J. Biol. Chem., February 9, 2007; 282(6): 4136 - 4151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kondoh, K. Sunadome, and E. Nishida Notch Signaling Suppresses p38 MAPK Activity via Induction of MKP-1 in Myogenesis J. Biol. Chem., February 2, 2007; 282(5): 3058 - 3065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schubert-Unkmeir, O. Sokolova, U. Panzner, M. Eigenthaler, and M. Frosch Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis Infect. Immun., February 1, 2007; 75(2): 899 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Katou, K. Kuroda, S. Seo, Y. Yanagawa, T. Tsuge, M. Yamazaki, A. Miyao, H. Hirochika, and Y. Ohashi A Calmodulin-Binding Mitogen-Activated Protein Kinase Phosphatase is Induced by Wounding and Regulates the Activities of Stress-Related Mitogen-Activated Protein Kinases in Rice Plant Cell Physiol., February 1, 2007; 48(2): 332 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Li, D. A. Scott, E. Hatch, X. Tian, and S. L. Mansour Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development Development, January 1, 2007; 134(1): 167 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. V. Wattenberg Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis Am J Physiol Cell Physiol, January 1, 2007; 292(1): C24 - C32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fan, P. S. Yan, C. Hartman-Frey, L. Chen, H. Paik, S. L. Oyer, J. D. Salisbury, A. S.L. Cheng, L. Li, P. H. Abbosh, et al. Diverse Gene Expression and DNA Methylation Profiles Correlate with Differential Adaptation of Breast Cancer Cells to the Antiestrogens Tamoxifen and Fulvestrant Cancer Res., December 15, 2006; 66(24): 11954 - 11966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhou, J. Zhang, S. Liu, S. Reddy, F. Wang, and Z.-Y. Zhang Mapping ERK2-MKP3 Binding Interfaces by Hydrogen/Deuterium Exchange Mass Spectrometry J. Biol. Chem., December 15, 2006; 281(50): 38834 - 38844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Costa, M. Marchi, F. Cardarelli, A. Roy, F. Beltram, L. Maffei, and G. M. Ratto Dynamic regulation of ERK2 nuclear translocation and mobility in living cells J. Cell Sci., December 1, 2006; 119(23): 4952 - 4963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu and C. Jefcoate 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Epidermal Growth Factor Cooperatively Suppress Peroxisome Proliferator-Activated Receptor-{gamma}1 Stimulation and Restore Focal Adhesion Complexes during Adipogenesis: Selective Contributions of Src, Rho, and Erk Distinguish These Overlapping Processes in C3H10T1/2 Cells Mol. Pharmacol., December 1, 2006; 70(6): 1902 - 1915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Dickinson and S. M. Keyse Diverse physiological functions for dual-specificity MAP kinase phosphatases J. Cell Sci., November 15, 2006; 119(22): 4607 - 4615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chu and T. J. Ferro Identification of a hydrogen peroxide-induced PP1-JNK1-Sp1 signaling pathway for gene regulation Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L983 - L992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, J. Xu, J.-Y. Zhou, Y. Liu, and G. S. Wu Mitogen-Activated Protein Kinase Phosphatase-1 Is Required for Cisplatin Resistance. Cancer Res., September 1, 2006; 66(17): 8870 - 8877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Abraham, T. Lawrence, A. Kleiman, P. Warden, M. Medghalchi, J. Tuckermann, J. Saklatvala, and A. R. Clark Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1 J. Exp. Med., August 7, 2006; 203(8): 1883 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cui, I. Parra, M. Zhang, S. G. Hilsenbeck, A. Tsimelzon, T. Furukawa, A. Horii, Z.-Y. Zhang, R. I. Nicholson, and S. A.W. Fuqua Elevated Expression of Mitogen-Activated Protein Kinase Phosphatase 3 in Breast Tumors: A Mechanism of Tamoxifen Resistance Cancer Res., June 1, 2006; 66(11): 5950 - 5959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Granas, B. K. Lundholt, F. Loechel, H.-C. Pedersen, S. P. Bjorn, V. Linde, C. Krogh-Jensen, E.-M. D. Nielsen, M. Praestegaard, and S. J. Nielsen Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution(R) Screen J Biomol Screen, June 1, 2006; 11(4): 423 - 434. [Abstract] [PDF]
|
|
|
|
|
|
E. Sanchez-Tillo, M. Comalada, C. Farrera, A. F. Valledor, J. Lloberas, and A. Celada Macrophage-Colony-Stimulating Factor-Induced Proliferation and Lipopolysaccharide-Dependent Activation of Macrophages Requires Raf-1 Phosphorylation to Induce Mitogen Kinase Phosphatase-1 Expression. J. Immunol., June 1, 2006; 176(11): 6594 - 6602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Zhou, Y. Liu, and G. S. Wu The Role of Mitogen-Activated Protein Kinase Phosphatase-1 in Oxidative Damage-Induced Cell Death. Cancer Res., May 1, 2006; 66(9): 4888 - 4894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ivanov, C. Pellegrino, S. Rama, I. Dumalska, Y. Salyha, Y. Ben-Ari, and I. Medina Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons J. Physiol., May 1, 2006; 572(3): 789 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hu and N. F. Mivechi Association and Regulation of Heat Shock Transcription Factor 4b with both Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Dual-Specificity Tyrosine Phosphatase DUSP26 Mol. Cell. Biol., April 15, 2006; 26(8): 3282 - 3294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liu, J.-P. Sun, B. Zhou, and Z.-Y. Zhang Structural basis of docking interactions between ERK2 and MAP kinase phosphatase 3 PNAS, April 4, 2006; 103(14): 5326 - 5331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Yoshioka, A Boivin, P Ye, F Labrie, and J St-Amand Effects of dihydrotestosterone on skeletal muscle transcriptome in mice measured by serial analysis of gene expression. J. Mol. Endocrinol., April 1, 2006; 36(2): 247 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ouyang, J. A. Knauf, E. P. Smith, L. Zhang, T. Ramsey, N. Yusuff, D. Batt, and J. A. Fagin Inhibitors of Raf Kinase Activity Block Growth of Thyroid Cancer Cells with RET/PTC or BRAF Mutations In vitro and In vivo. Clin. Cancer Res., March 15, 2006; 12(6): 1785 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zaitseva, B. J. Vollenhoven, and P. A.W. Rogers In vitro culture significantly alters gene expression profiles and reduces differences between myometrial and fibroid smooth muscle cells Mol. Hum. Reprod., March 1, 2006; 12(3): 187 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hayakawa, Y. Meng, N. Hiramatsu, A. Kasai, K. Yamauchi, J. Yao, and M. Kitamura Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli J. Immunol., February 15, 2006; 176(4): 2529 - 2537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-W. Lin and J.-L. Yang Cooperation of ERK and SCFSkp2 for MKP-1 Destruction Provides a Positive Feedback Regulation of Proliferating Signaling J. Biol. Chem., January 13, 2006; 281(2): 915 - 926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mazurek, Y. J. Sun, J. E. Price, L. Ramdas, W. Schober, P. Nangia-Makker, J. C. Byrd, A. Raz, and R. S. Bresalier Phosphorylation of Galectin-3 Contributes to Malignant Transformation of Human Epithelial Cells via Modulation of Unique Sets of Genes Cancer Res., December 1, 2005; 65(23): 10767 - 10775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Belcher, H. H. Le, L. Spurling, and J. K. Wong Rapid Estrogenic Regulation of Extracellular Signal- Regulated Kinase 1/2 Signaling in Cerebellar Granule Cells Involves a G Protein- and Protein Kinase A-Dependent Mechanism and Intracellular Activation of Protein Phosphatase 2A Endocrinology, December 1, 2005; 146(12): 5397 - 5406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Katou, E. Karita, H. Yamakawa, S. Seo, I. Mitsuhara, K. Kuchitsu, and Y. Ohashi Catalytic Activation of the Plant MAPK Phosphatase NtMKP1 by Its Physiological Substrate Salicylic Acid-induced Protein Kinase but Not by Calmodulins J. Biol. Chem., November 25, 2005; 280(47): 39569 - 39581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. R. Wong, K. E. Dunsmore, K. Page, and T. P. Shanley Heat shock-mediated regulation of MKP-1 Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1152 - C1158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, Q. Yang, M. Shen, X. Huang, M. Dembski, R. Gimeno, L. A. Tartaglia, R. Kapeller, and Z. Wu Dual Specificity MAPK Phosphatase 3 Activates PEPCK Gene Transcription and Increases Gluconeogenesis in Rat Hepatoma Cells J. Biol. Chem., October 28, 2005; 280(43): 36013 - 36018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Christie, D. J. Williams, F. MacIsaac, R. J. Dickinson, I. Rosewell, and S. M. Keyse The Dual-Specificity Protein Phosphatase DUSP9/MKP-4 Is Essential for Placental Function but Is Not Required for Normal Embryonic Development Mol. Cell. Biol., September 15, 2005; 25(18): 8323 - 8333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hezi-Yamit, P. W. Wong, N. Bien-Ly, L. G. Komuves, K. S. S. Prasad, D. R. Phillips, and U. Sinha Synergistic induction of tissue factor by coagulation factor Xa and TNF: Evidence for involvement of negative regulatory signaling cascades PNAS, August 23, 2005; 102(34): 12077 - 12082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Kovanen, L. Young, A. Al-Shami, V. Rovella, C. A. Pise-Masison, M. F. Radonovich, J. Powell, J. Fu, J. N. Brady, P. J. Munson, et al. Global analysis of IL-2 target genes: identification of chromosomal clusters of expressed genes Int. Immunol., August 1, 2005; 17(8): 1009 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nyunoya, M. M. Monick, L. S. Powers, T. O. Yarovinsky, and G. W. Hunninghake Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation J. Biol. Chem., July 15, 2005; 280(28): 26295 - 26302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Willoughby and M. K. Collins Dynamic Interaction between the Dual Specificity Phosphatase MKP7 and the JNK3 Scaffold Protein {beta}-Arrestin 2 J. Biol. Chem., July 8, 2005; 280(27): 25651 - 25658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. McMullen, P. W. Bryant, C. C. Glembotski, P. A. Vincent, and K. M. Pumiglia Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells J. Biol. Chem., June 3, 2005; 280(22): 20995 - 21003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Wu, L. Zhang, and A. M. Bennett The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase 1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation Mol. Cell. Biol., June 1, 2005; 25(11): 4792 - 4803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Brancho, J.-J. Ventura, A. Jaeschke, B. Doran, R. A. Flavell, and R. J. Davis Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades Mol. Cell. Biol., May 1, 2005; 25(9): 3670 - 3681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Wu and A. M. Bennett Essential Role for Mitogen-activated Protein (MAP) Kinase Phosphatase-1 in Stress-responsive MAP Kinase and Cell Survival Signaling J. Biol. Chem., April 22, 2005; 280(16): 16461 - 16466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Katagiri, K. Masuda, T. Urano, K. Yamashita, Y. Araki, K. Kikuchi, and H. Shima Phosphorylation of Ser-446 Determines Stability of MKP-7 J. Biol. Chem., April 15, 2005; 280(15): 14716 - 14722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-H. Lee, C.-T. Lee, Y. W. Kim, S. K. Han, Y.-S. Shim, and C.-G. Yoo Preheating Accelerates Mitogen-activated Protein (MAP) Kinase Inactivation Post-heat Shock via a Heat Shock Protein 70-mediated Increase in Phosphorylated MAP Kinase Phosphatase-1 J. Biol. Chem., April 1, 2005; 280(13): 13179 - 13186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Hancock, S. Dangi, and P. Shapiro Protein Phosphatase 2A Activity Associated with Golgi Membranes during the G2/M Phase May Regulate Phosphorylation of ERK2 J. Biol. Chem., March 25, 2005; 280(12): 11590 - 11598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nazarian, K. Bouri, and E. P. Hoffman Intracellular expression profiling by laser capture microdissection: three novel components of the neuromuscular junction Physiol Genomics, March 21, 2005; 21(1): 70 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Subramaniam, N. Shahani, J. Strelau, C. Laliberte, R. Brandt, D. Kaplan, and K. Unsicker Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway J. Neurosci., March 16, 2005; 25(11): 2838 - 2852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mandl, D. N. Slack, and S. M. Keyse Specific Inactivation and Nuclear Anchoring of Extracellular Signal-Regulated Kinase 2 by the Inducible Dual-Specificity Protein Phosphatase DUSP5 Mol. Cell. Biol., March 1, 2005; 25(5): 1830 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ludwig, J. Mages, C. Staib, M. H. Lehmann, R. Lang, and G. Sutter Role of Viral Factor E3L in Modified Vaccinia Virus Ankara Infection of Human HeLa Cells: Regulation of the Virus Life Cycle and Identification of Differentially Expressed Host Genes J. Virol., February 15, 2005; 79(4): 2584 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hardy, L. Mansfield, A. Mackay, S. Benvenuti, S. Ismail, P. Arora, M. J. O'Hare, and P. S. Jat Transcriptional Networks and Cellular Senescence in Human Mammary Fibroblasts Mol. Biol. Cell, February 1, 2005; 16(2): 943 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Qin, X. Li, J.-K. Ko, and N. C. Partridge Parathyroid Hormone Uses Multiple Mechanisms to Arrest the Cell Cycle Progression of Osteoblastic Cells from G1 to S Phase J. Biol. Chem., January 28, 2005; 280(4): 3104 - 3111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marchetti, C. Gimond, J.-C. Chambard, T. Touboul, D. Roux, J. Pouyssegur, and G. Pages Extracellular Signal-Regulated Kinases Phosphorylate Mitogen-Activated Protein Kinase Phosphatase 3/DUSP6 at Serines 159 and 197, Two Sites Critical for Its Proteasomal Degradation Mol. Cell. Biol., January 15, 2005; 25(2): 854 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Furst, C. Brueckl, W. M. Kuebler, S. Zahler, F. Krotz, A. Gorlach, A. M. Vollmar, and A. K. Kiemer Atrial Natriuretic Peptide Induces Mitogen-Activated Protein Kinase Phosphatase-1 in Human Endothelial Cells via Rac1 and NAD(P)H Oxidase/Nox2-Activation Circ. Res., January 7, 2005; 96(1): 43 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. H. Shah, J. A. Olivares-Reyes, and K. J. Catt The Protein Kinase C Inhibitor Go6976 [12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Potentiates Agonist-Induced Mitogen-Activated Protein Kinase Activation through Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor Mol. Pharmacol., January 1, 2005; 67(1): 184 - 194. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, the microtubule regulator stathmin, cytosolic
phospholipase A2 (cPLA2), as well as the downstream target kinases MAP
kinase-activated protein kinase-1 (MAPKAP-K1, also known as ribosomal
p90 S6 kinase or RSK), mitogen- and stress-activated protein kinase-1
(MSK-1), MAPKAP-K2, MAPKAP-K3, MAP kinase-integrating kinase-1 (Mnk1),
and Mnk2. MAP kinase kinase activation (broken arrows) is mediated by
numerous upstream kinases acting together with various GTP binding
proteins as well as complex-forming adaptor proteins
(3
