M I N I R E V I E WRegulation of stress-activated protein kinase signaling pathways by protein phosphatases Shinri Tamura, Masahito Hanada, Motoko Ohnishi, Koji Katsura, Masato Sasaki an
Trang 1M I N I R E V I E W
Regulation of stress-activated protein kinase signaling pathways
by protein phosphatases
Shinri Tamura, Masahito Hanada, Motoko Ohnishi, Koji Katsura, Masato Sasaki and Takayasu Kobayashi Department of Biochemistry, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Japan
Stress-activated protein kinase (SAPK) signaling plays
essential roles in eliciting adequate cellular responses to
stresses and proinflammatory cytokines SAPK pathways
are composed of three successive protein kinase reactions
The phosphorylation of SAPK signaling components on
Ser/Thr or Thr/Tyr residues suggests the involvement of
various protein phosphatases in the negative regulation of
these systems Accumulating evidence indicates that three
families of protein phosphatases, namely the Ser/Thr
phosphatases, the Tyr phosphatases and the dual
specif-icity Ser/Thr/Tyr phosphatases regulate these pathways, each mediating a distinct function Differences in substrate specificities and regulatory mechanisms for these phos-phatases form the molecular basis for the complex regulation of SAPK signaling Here we describe the properties of the protein phosphatases responsible for the regulation of SAPK signaling pathways
Keywords: stress response; stress-activated protein kinase; protein phosphatase
I N T R O D U C T I O N
Stress-activated protein kinases (SAPKs), a subfamily of the
mitogen-activated protein kinase (MAPK) superfamily, are
highly conserved from yeast to mammals SAPKs relay
signals in response to various extracellular stimuli, including
environmental stresses and proinflammatory cytokines In
mammalian cells, two distinct classes of SAPKs have been
identified, the c-Jun N-terminal kinases (JNK) and the p38
MAPKs [1,2] (Fig 1)
The activation of SAPKs requires phosphorylation of
conserved tyrosine and threonine residues within the
catalytic domain This phosphorylation is mediated by dual
specificity protein kinases, members of the MAPK kinase
(MKK) family MKK3 and MKK6 are specific for p38,
MKK7 selectively phosphorylates JNK, and MKK4
recognizes either class of the stress actived kinases (Fig 1)
The MKKs are also activated by the phosphorylation of
conserved serine and threonine residues [1,2] Several
MKK-activating MKK kinases (MKKKs) have been
identified, some of which are activated again by phosphory-lation [3,4] In the absence of a signal, the constituents of the SAPK cascade return to their inactive, dephosphorylated state, suggesting an essential role for phosphatases in SAPK regulation
Protein phosphatases are classified into three groups, Ser/Thr phosphatases, Ser/Thr/Tyr phosphatases and Tyr phosphatases, depending on their phosphoamino-acid specificity The dephosphorylation of SAPK signal pathway components on either Ser/Thr or Thr/Tyr residues requires the participation of various phosphatases In this article, we first review the roles of protein phosphatases in the regulation of yeast SAPK pathways, then focus on the properties of the protein phosphatases implicated in the mammalian SAPK systems
R E G U L A T I O N O F S A P K S I G N A L
P A T H W A Y S B Y P R O T E I N
P H O S P H A T A S E S I N Y E A S T C E L L S
A molecular genetic analysis of yeast cells indicated that two distinct protein phosphatase groups, protein Tyr phospha-tases (PTP) and protein Ser/Thr phosphaphospha-tases of type 2C (PP2C), act as negative regulators of SAPK pathways [5,6]
In the budding yeast, Saccharomyces cerevisiae, hyper-osmotic shock activates the SSK2/SSK22 (MKKK)-Pbs2 (MKK)-Hog1 (SAPK) kinases In the fission yeast, Schizosaccharomyces pombe, heat shock, oxidative stress, nutrient stress and osmotic shock all induce the Wik1 (MKKK)-Wis1 (MKK)-Spc1 (SAPK) pathway; the activa-ted Spc1 in turn changes gene expression through the activation of the Atf1 transcription factor [7–10]
The PTPs of S cerevisiae (Ptp2 and Ptp3) and S pombe (Pyp1 and Pyp2) suppress the SAPK pathways, as demon-strated by molecular genetic studies [5,8,10–12] In S pombe, Pyp2 dephosphorylates the tyrosine residue of Spc1 both
in vivoand in vitro [8,12] Extracellular stress induces expres-sion of the pyp2 gene in an Spc1-Atf1-dependent manner
Correspondence to S Tamura, Department of Biochemistry, Institute
of Development, Aging and Cancer, Tohoku University 4-1
Seiryomachi, Aoba-ku, Sendai 980-8575, Japan.
Fax: + 81 22 717 8476, Tel.: + 81 22 717 8471,
E-mail: tamura@idac.tohoku.ac.jp
Abbreviations: SAPK, stress-activated protein kinase; MAPK,
mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase;
MKK, MAPK kinase; MKKK, MKK kinase; PTP, protein Tyr
phosphatase; PP, protein Ser/Thr phosphatase; DSP, dual specificity
protein phosphatase; MKP, MAPK phosphatase; ERK,
extracellu-lar signal-regulated kinase; TPA, 12-O-tetradecanoylphorbol
13-acetate; TCR, T cell receptor; TGF-b, transforming growth
factor-b; TAK1, TGF-b-activated kinase 1; IL-1, interleukin-1;
KIM, kinase interaction motif; PA,
1,2-dioleoyl-sn-glycero-3-phosphate.
(Received 6 August 2001, accepted 20 September 2001)
Trang 2[10,11] In addition, PP2C (Ptc1 and Ptc3 of S cerevisiae
and Ptc1 and Ptc3 of S pombe) acts as a negative regulator
of SAPK pathways [13–15] In S pombe, Ptc1 acts upon a
target downstream of SAPK (Spc1) [6] When Spc1
enhances the expression of Atf1, this up-regulation induces
Ptc1 expression, suppressing Atf1 function Ptc1 and Ptc3
directly dephosphorylate the threonine of Spc1, but not the
tyrosine [16] In addition, Ptc1 dephosphorylates Hog1 in S
cerevisiae both in vivo and in vitro [15]
R E G U L A T I O N O F S A P K S I G N A L
P A T H W A Y S B Y P R O T E I N
P H O S P H A T A S E S I N M A M M A L I A N C E L L S
In mammalian cells, like yeast cells, both PTP and PP2C
regulate the SAPK signal pathways [17–23] Mammalian
cells are unique in several respects as, in addition to PTP and
PP2C, they contain a large family of dual specificity protein
phosphatases (DSP) that negatively influence the SAPK
pathways [24] Although the participation of a DSP, MSG5,
in the negative regulation of mating hormone-induced
MAPK (Fus3p) activation is well documented [25], the
parti-cipation of such DSPs in the regulation of the yeast SAPK
system has not been observed In addition, protein
phospha-tase 2A (PP2A) may also function in the regulation of the
mammalian SAPK pathway [26] In this section, we describe
the properties of mammalian protein phosphatase
mole-cules involved in the regulation of SAPK signal pathways
Dual specificity protein phosphatases
The gene products of at least 10 distinct DSP genes share two
unique structural features; they contain a common active site
sequence motif [VXVHCXXGXSRSXTXXX AY(L/I)M]
and two N-terminal CH2 domains, homologous to the cell
cycle regulator Cdc25 [27] DSP substrate studies indicate
that MAPK phosphatase-3 (MKP-3) specifically
dephosph-orylates extracellular signal-regulated kinase (ERK) but not JNK or p38 [27,28] In contrast, both MKP-5 and M3/6 dephosphorylate both JNK and p38 but not ERK (Table 1) [27,29,30] The high specificity of MKP-2 for ERK and JNK (but not for p38) and that of PAC-1 for ERK and p38 (but not for JNK) has been reported (Table 1) [31] On the other hand, MKP-1 and MKP-4 were found to dephosphorylate ERK, JNK and p38 [31,32] These facts indicate an unexpected complexity for the negative regulation of the MAP kinase signaling In the forthcoming paragraphs we present a detailed description of the mammalian DSPs involved in the regulation of SAPK signaling pathways MKP-1 (CL100) MKP-1, a protein of 39.5 kDa, is expressed upon oxidative stress and heat shock in human skin cells [33] MKP-1 mRNA is ubiquitously expressed in various tissues, with the protein product localized preferen-tially to the cell nucleus [34] This enzyme acts as a DSP, dephosphorylating both threonine and tyrosine residues of ERK, JNK and p38 [31,35] In addition to oxidative stress and heat shock, MKP-1 is induced by various stimuli such
as, osmotic shock, anisomycin, growth factors, UV, 12-O-tetradecanoylphorbol 13-acetate (TPA), Ca2+ionophores and lipopolysaccharide [33–42] MKP-1 expression is part
of a feed back mechanism: the activation of MAPKs induces MKP-1; that in turn inactivates MAPKs The details of the regulatory mechanism depend on the cell lineage In vascular smooth muscle cells, mesangial cells and U937 cells, the activation of either ERK, JNK or p38 induces MKP-1; in NIH3T3 cells, the activation of JNK but not ERK up-regulates MKP-1 expression [35,37,40,43–45]
In addition, activation of p38 but not ERK or JNK enhances MKP-1 induction in H4IIE hepatoma cells [36] In Rat1 fibroblasts, MKP-1 is induced by Ca2+ signaling, independently of MAPK activation [41] In this context,
Ca2+/calmodulin-activated protein phosphatase (PP2B) participates in the induction of MKP-1 in cardiac myocytes
Fig 1 SAPK signaling modules The protein
kinase cascades of SAPK signaling pathways
and the points where the phosphatases can
interfere with the signals are shown MKKK,
MKK kinase; MKK, MAPK kinase; MAPK,
MAP kinase; TAK1, TGF-b-activated kinase
1; MEKK, MEK kinase; MLK, mixed lineage
kinase; ASK1, apoptosis signal-regulating
kinase 1; JNK, c-Jun N-terminal kinase.
Trang 3[46] MKP-1 binds to C-terminal region of p38, that results
in its activation [34] The stability of MKP-1 is regulated by
ERK-mediated phosphorylation of two C-terminal serine
residues [47] This phosphorylation, while not modifying the
intrinsic activity of MKP-1, stabilizes the protein
MKP-2 (hVH2) MKP-2, a 42.6-kDa nuclear DSP, is
widely expressed in various tissues [48] This phosphatase is
highly specific for ERK and JNK, but not p38 [31] MKP-2
is induced by nerve growth factor, TPA and hepatocyte
growth factor in PC12 cells, peripheral blood T cells and
MDCK cells, respectively [31,49,50] In MDCK cells,
hepatocyte growth factor-activated ERK induces MKP-2
expression; that inactivates JNK, which has also been
activated by GF, by dephosphorylation [50]
Overexpres-sion of v-Jun, a constitutively active form of c-Jun, enhances
the expression of MKP-2 mRNA in chick embryo
fibro-blasts [51] Therefore, the activation of JNK may also
influence in MKP-2 expression
MKP-4.MKP-4 is a DSP of 41.8 kDa displaying moderate
substrate specificity for ERK over JNK or p38 [32]
Immunostaining of MKP-4 expressed in either NIH3T3
cells or COS7 cells revealed that MKP-4 is localized mainly
to the cytoplasm; a subset of cells, however, also displays a
punctuate nuclear staining [32] Expression of MKP-4
mRNA is highly restricted to the placenta, kidney and
embryonic liver [32] Phosphatase activation is mediated by
substrate binding [52]
MKP-5 MKP-5, a widely expressed 52.6-kDa protein,
preferentially dephosphorylates both JNK and p38, and
demonstrates extremely low activity against ERK [29,30]
This enzyme is evenly localized throughout the cytoplasm
and nucleus [29] In cultured cells, the expression of MKP-5
is elevated by stress stimuli such as anisomycin and osmotic
stress but not by UV irradiation [29] MKP-5 binds to p38
and JNK, but not ERK [29,30]
MKP-6 MKP-6 (25 kDa) was found as a CD28 (T cell
costimulatory receptor) binding protein [53] In vitro,
MKP-6 dephosphorylates ERK, JNK and p38 However, expres-sion of a dominant negative form of MKP-6 in T cells further stimulates the T cell receptor (TCR)/CD28-enhanced phosphorylation of both ERK and JNK but not p38, suggesting that ERK and JNK are the preferred substrates of MKP-6 in the cells MKP-6 expression is up-regulated by CD28 costimulation of T cells Binding of the expressed MKP-6 to CD28 is required for the feed back regulation of ERK and JNK by MKP-6 [53]
M3/6 (hVH5) M3/6 was the first DSP found to selectively inhibit stress-induced activation of JNK and p38; M3/6 does not, however, affect growth factor-induced activation of ERK in mammalian cells [27] In K562 human leukemia cells, hVH5 (human orthologue of mouse M3/6) mRNA levels are rapidly enhanced by TPA treatment [54] The induction of exogenous M3/6 inhibited TPA-stimulated phosphorylation of JNK and p38, sug-gesting a feedback loop governing SAPK activity The activation of JNK stimulates the phosphorylation of M3/6; unlike MKP-1, however, the phosphorylation of M3/6 does not regulate its half life [54] An internal motif, XILPXL(Y/F)LG, homologous to the SAPK binding site
of c-Jun (delta domain), is important for M3/6 activity [54]
PAC-1.PAC-1 is a DSP of 32 kDa, originally found to be expressed predominantly in hematopoietic cells [55] Subse-quently, induction of PAC-1 mRNA in hippocampus neurons following forebrain ischemia or kainic acid-induced seizure has been reported [56,57] PAC-1 dephosphorylates both ERK and p38 but not JNK [31] Activation of ERK induces the enhanced-expression of PAC-1 and the expressed PAC-1 then inactivates ERK in T cells [58] Protein phosphatase 2C
Protein phosphatase 2C (PP2C) is one of the four major protein serine/threonine phosphatases (PP1, PP2A, PP2B and PP2C) in eukaryotes At least six distinct PP2C gene products (2Ca, 2Cb, 2Cc, 2Cd, Wip1 and Ca2+ /calmodu-lin-dependent protein kinase phosphatase) operate in mammalian cells [59–65] Studies of mammalian PP2C function indicated that PP2Ca, PP2Cb and Wip1 are involved in the negative regulation of SAPK cascades [20– 23] In addition, PP2Ca and PP2Cb may regulate cell cycle progression [66] PP2Ca is implicated in Wnt signaling regulation [67] Here, we describe the properties of PP2C isoforms regulating the SAPK signal pathways
PP2Ca PP2Ca, a 42-kDa phosphatase, was first cloned from a rat kidney cDNA library [59] The existence of two distinct human PP2Ca isoforms (a-1 and a-2), differing at their C-terminal regions, was subsequently reported [20,68]
A cDNA clone encoding PP2Ca-2 was isolated in the screening of a human cDNA library for genes down-regulating the yeast Hog1 MAPK pathway [20] When expressed in mammalian cells, PP2Ca-2 inhibits stress-induced activation of p38 and JNK, but does not affect mitogen-induced activation of ERK Mouse PP2Ca, cor-responding to human PP2Ca-1, exhibited a similar inhibi-tion pattern [21] PP2Ca-2 dephosphorylates and inactivates MKK4, MKK6 and p38 both in vivo and in vitro [20]
Table 1 Protein phosphatases involved in regulation of SAPK signal
pathways.
Phosphatase Substrate References
DSP family
MKP-1 (CL100, 3CH134) JNK, p38, ERK [31,35]
MKP-2 (hVH2, Typ-1) JNK, ERK [31]
MKP-4 JNK, p38, ERK [32]
MKP-5 JNK, p38 [29,30]
MKP-6 JNK, ERK [55]
M3/6 (hVH5) JNK, p38 [27]
PAC-1 p38, ERK [31]
PP2C family
PP2Ca-2 MKK4, MKK6, p38 [20]
PTP family
HePTP/LC-PTP p38, ERK [17,18]
PTP-SL/STEP p38, ERK [19,78]
PP2A family
Trang 4Furthermore PP2Ca-2 specifically associates with
phos-phorylated p38
PP2Cb The PP2Cb gene encodes at least six distinct
isoforms (43 kDa), which are splicing variants of a single
premRNA [60,69–71] These isoforms differ only at the
C-terminal regions PP2Cb-1 is expressed ubiquitously in
various tissues, while PP2Cb-2 expression is restricted to the
brain and heart PP2Cb-3, -4 and -5 transcripts were
detec-ted predominantly in the liver, testes and intestine [69,70] In
mammalian cells, PP2Cb-1 selectively suppresses the
stress-induced activation of p38 and JNK but has no effect on the
mitogen-induced activation of ERK [21] Investigation of
the PP2Cb-1-mediated suppression of the SAPK pathway
revealed that PP2Cb-1 dephosphorylates and inactivates
transforming growth factor-b (TGF-b)-activated kinase
(TAK1), a MKKK activated either by stress, TGF-b
treat-ment or interleukin-1 (IL-1) stimulation [23] In addition,
PP2Cb-1 selectively associates with TAK1 in a stable
com-plex Expression of a dominant-negative form of PP2Cb-1
enhances the IL-1-induced activation of AP-1 reporter gene,
suggesting PP2Cb-1 negatively regulates TAK1 signaling
through the dephosphorylation of TAK1 in vivo [23]
Wip1 Wip1, a 61-kDa Mg2+-dependent protein
phospha-tase, is induced by ionizing radiation in a p53-dependent
manner [64] It is localized to the nucleus, the nuclear levels
of Wip1 increase in response to the ionizing irradiation
The expression of Wip1 is also induced by treatment with
methyl methane sulfonate, H2O2 or anisomycin [22]
Functional studies of Wip1 revealed its role in the
down-regulation of p38/p53-induced signaling during the recovery
of damaged cells [22] Thus, the induction of Wip1 by stress
selectively blocks the activation of p38, and suppresses
subsequent p53 activation In vitro, Wip1 inactivates p38 by
the specific dephosphorylation of a conserved threonine
residue; however, it does not accept ERK, JNK, MKK4 or
MKK6 as a substrate [22]
Other protein phosphatases
Recently evidence has emerged suggesting the participation
of okadaic acid-sensitive protein phosphatases and PTPs in
the regulation of mammalian SAPK pathways [17–19,26]
In this section, we describe the roles of protein phosphatase
2A (PP2A) and tyrosine phosphatases, HePTP/LC-PTP
and PTP-SL/STEP, in SAPK signaling
PP2A Addition of okadaic acid to the culture medium
enhanced the lipopolysaccharide-induced activation of JNK
in THP-1 cells (a human acute monocytic leukemia cell line)
[26] In addition the regulatory subunit of PP2A, PP2A-Aa,
coprecipitates with JNK [26] JNK activity was unaffected
by specific pharmacological inhibition of protein
phospha-tase 1 by 1,2-dioleoyl-sn-glycero-3-phosphate (PA); the
activation of PP2A by high doses of PA, however, decreased
JNK activity [26] These results suggest that PP2A may
suppress the lipopolysaccharide-induced JNK through the
direct dephosphorylation of JNK
HePTP/LC-PTP HePTP and LC-PTP are closely related
human cytosolic PTPs, predominantly expressed in
hem-opoietic cells [17,18] In T lymphocytes, the transcription of
HePTP is enhanced by IL-2 treatment [72] When expressed
in Jurkat T cells, HePTP/LC-PTP inhibits the TCR-induced activation of both ERK and p38, but not JNK [17,18] Both ERK and p38 (but not JNK) associate with the kinase interaction motif (KIM) in the N-terminal segment of HePTP/LC-PTP The phosphorylation of HePTP by PKA inhibits its association with ERK and p38 [73] Conse-quently the PKA-mediated release of the phosphatase activates both ERK and p38
PTP-SL/STEP PTP-SL and STEP are non-nuclear PTPs, which exist in transmembrane and cytosolic forms and are mainly expressed in neuronal cells [74–77] PTP-SL dephosphorylates both ERK and p38 [19,78] Like HePTP, PTP-SL associates with ERK and p38 but not with JNK through its KIM located in the juxtamembrane region [78] The phosphorylation of PTP-SL by PKA was found to inhibit its association with ERK and p38, and the subsequent tyrosine dephosphorylation of these MAPKs [19]
C O N C L U S I O N S A N D P E R S P E C T I V E S Numerous phosphatase molecules are capable of negatively regulating SAPK signaling pathways (summarized in Table 1 and Fig 1) including the members of four distinct groups: DSP, PP2C, PP2A and PTP Regulation of a single substrate by multiple protein phosphatases suggests redundancy Alternatively, the level of phosphorylation in each protein component of the SAPK pathway may be regulated by multiple upstream signals functioning via distinct protein phosphatases
We conclude that at least two distinct mechanisms can operate in the regulation The expression of phosphatases, such as MKP-1, MKP-2, MKP-5, M3/6, PTC-1, Wip1 and HePTP, is positively regulated through the activation
of MAP kinases In addition, some phosphatases are regulated by direct association with MAPKs For example both MKP-1 and MKP-4 are activated via binding to their MAPK substrates [34,52] Direct association was also observed between MKP-5 and p38 or JNK [29,30] Interestingly, a sequence motif, XILPXL(Y/F)LG, which
is similar to a delta domain consensus motif critical for binding to JNK and ERK in other proteins, is converved
in all of these DSPs The delta-like domain is located N-terminal to the catalytic consensus sequence of the DSPs The delta-like domain is also conserved in M3/6; deletion of this sequence blocks the ability of M3/6 to dephosphorylate JNK [54] These results suggest that the delta-like domain is involved in the association of phosphatases with MAPKs Another association between MAPKs and HePTP/LC-PTP or PTP-SL/STEP phos-phatases and regulation of this association by PKA is also
of great importance [19,73]
Substrate specificity studies indicated that several mem-bers of the DSP and PTP families dephosphorylate both ERK and JNK/p38 (Table 1) This suggests that phospha-tases may mediate the signaling between the ERK and SAPK pathways Future studies will certainly clarify the significance of such cross-talk between the ERK and SAPK pathways via protein phosphatases
The protein phosphatases that dephosphorylate MKKs and MKKKs have not been well investigated The PP2C
Trang 5family may play a central role in the regulation of these
kinases as PP2Ca-2 dephosphorylates both MKK4 and
MKK6 [20] In addition, PP2Cb-1 dephosphorylates
TAK1, but not MKK6 [23] These results suggest that each
isoform of PP2C may have a distinct specificity for
substrates in SAPK pathways Future studies are required
for identification of phosphatases responsible for
dephos-phorylation of other MKK and MKKK members
A C K N O W L E D G E M E N T
The authors are grateful to Dr Masato Ogata (Osaka University) for
critically reviewing this article.
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