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(Received for publication, February 21, 1997, and in revised form, April 17, 1997)
From the The Kennedy Institute of Rheumatology, 1 Aspenlea Road,
Hammersmith, London W6 8LH, United Kingdom
ABSTRACT Interleukin-2 (IL-2) is a potent T cell mitogen.
However, the signaling pathways by which IL-2 mediates its mitogenic
effect are not fully understood. One of the members of the
mitogen-activated protein kinase (MAPK) family, p42/44MAPK (ERK2/1), is
known to be activated by IL-2. We have now investigated the response to IL-2 of two other members of the MAP kinase family, p54MAP kinase (stress-activated protein kinase (SAPK)/Jun-N-terminal kinase (JNK))
and p38MAP kinase (p38/Mpk2/CSBP/RK), which respond primarily to
stressful and inflammatory stimuli (e.g. tumor necrosis
factor- INTRODUCTION Interleukin-2 (IL-2)1 is a key factor
in driving the proliferation of activated T lymphocytes; a crucial
event in mounting an effective immune response (1). The high affinity
IL-2 receptor is a heterotrimeric complex composed of Ligation of IL-2 to its receptor initiates the activation of several
intracellular enzymes including the tyrosine kinases: Jak1, Jak3 (3,
4), Syk (5) and p56lck (6); phosphatidylinositol 3 The apparent redundancy of ERK activation in T cell proliferation is in
contrast to other cellular systems, where these kinases have been
implicated in mitogenic responses to growth factors (33). This
functional link is supported by the transforming potential of the
proximal activators of this pathway, i.e. oncogenic Ras
(reviewed in Ref. 34) and Raf (35) and a constitutively active form of
MEK1 (36), as well as by studies with dominant-negative and antisense
cDNA (37). The inhibition of fibroblast proliferation by a specific
inhibitor of MEK1, PD098059 (38), further supports a role for this
pathway in proliferation.
Recently two other subgroups of the MAP kinase family have been
characterized, SAPK/JNK and p38MAP kinase. These kinases respond to a
variety of physicochemical stresses (e.g. UV light,
translational inhibitors, hyperosmolarity), lipopolysaccharide, and
the pro-inflammatory cytokines TNF- Unlike ERK, these "stress kinases" have not been implicated
previously in mitogenesis. The response of these enzymes to IL-2, other
T cell growth factors, or other cytokines barring those mentioned above
has not been investigated previously, although SAPK/JNK has been shown
to be activated in T cells by co-stimulation through CD3 and CD28 (44).
This study shows that both SAPK/JNK and p38MAP kinase are activated by
IL-2. In addition (which is not the case for ERK) they are also
activated by IL-7. The inhibition of p38MAP kinase activity by the
specific inhibitor SB203580 resulted in suppression of T cell
proliferation in response to IL-2 and IL-7, suggesting that rather than
being solely involved in stress responses, in T cells at least, p38MAP
kinase is required to transduce the mitogenic signal.
EXPERIMENTAL PROCEDURES IL-7 and IL-2 were kindly provided by Dr. C. Faltynek (Sterling Winthrope, Malvern, PA) and Dr. P. Lomedico, (Roche
Inc., Nutley, NJ), respectively. Rabbit antisera to SAPK/JNK were
raised to the N-terminal peptide sequence, GVVKGQPSPSAQVQQ, and to
p38MAP kinase as reported previously (45). Antibody to MAPKAP kinase-2 was from Upstate Biotechnology, Inc. (Lake Placid, NY), ERK was from
Santa Cruz (Santa Cruz, CA) and c-Myc was generously provided by Dr. G. Evan (Imperial Cancer Research Fund, London). The p38MAPK inhibitor
SB203580 was generously provided by Dr. J. Lee, SmithKline Beecham
Pharmaceuticals (King of Prussia, PA). GST-Jun (2-89) and GST-ATF2
(19-96) were purified by standard techniques.
The murine
cytokine-dependent T cell line, CT6 (kindly provided by
Genentech, South San Francisco, CA) was maintained and proliferation
assays and Western immunoblotting c-Myc and ERK performed as described
previously (14, 46). Cell viability was assessed by the amount of
merocyanine 540 (Sigma) incorporated into the cell membrane of live
gated cells (47). Human peripheral blood T cell isolation and
proliferation were as described previously (48). SB203580 was added to
the cells 15 min prior to the addition of cytokine where indicated.
Cells were
lysed at approximately 20 × 106/ml in 25 mM HEPES, pH 7.4, 50 mM In vitro kinase assays
for SAPK/JNK were performed on immunoprecipitates resuspended in 50 µl of assay buffer and 30 µl of 0.1 mg/ml GST-ATF2-(19-96) or
GST-JUN-(2-89). Reactions were initiated by addition of 10 µl of 180 µM ATP containing 0.5 µCi [ For the in vitro kinase assays for p38MAP kinase, Hsp27
kinase (which is similar, if not identical to MAPKAP kinase-2) and Hsp27 were purified from KB cells, and recombinant Hsp27 was prepared as described previously (41). To the immunoprecipitates were added 35 µl of kinase assay buffer, 30 µl of Hsp27 kinase (MAPKAP kinase-2),
which had been previously inactivated by treatment with protein
phosphatase 2A, and Hsp27 (1.5 µg/track); the reaction was initiated
and terminated as for the SAPK/JNK assays. All products were separated
by SDS-polyacrylamide gel electrophoresis, and dried gels were
autoradiographed at For the in vitro MAPKAP kinase-2 assays, the activated
enzyme was immunoprecipitated from lysates of 5-10 × 106 cell equivalents for 3 h at 4 °C. The
immunoprecipitates washed as for the p38MAP kinase and SAPK/JNK assays,
resuspended in 50 µl of kinase assay buffer containing 30 µM final concentration of Hsp27 peptide (sequence
KKLNRTLSVA (49)). Reactions were initiated with 10 µl of 180 µM ATP containing 0.5 µCi of
[ RESULTS SAPK/JNK activation was
measured by phosphorylation of GST Jun-(2-89) (43) or
GST-ATF-2-(19-96) (50) as substrates, after immunoprecipitation from
human (Kit-225) and murine (CT6) T cells. The enzyme was activated when
precipitated from IL-2-treated cells, as compared with that from
unstimulated cells (Fig. 1, a and
b). Treatment of the responsive CT6 cells with IL-7 also
activated this kinase (Fig. 1b). SAPK/JNK activation was
dose-dependent for both cytokines (Fig. 1, c and
d) and was maximal at 2 ng/ml (100 pM). This
correlates with the proliferative response of CT6 to either cytokine
(46). As expected, activated SAPK/JNK was also immunoprecipitated from
T cells stressed with anisomycin (Fig. 1a) or exposed to
TNF-
Generally, stressful and inflammatory stimuli that
activate SAPK/JNK also activate a related enzyme, p38MAP kinase. We
therefore investigated whether this second stress kinase would respond
to T cell mitogens. The activity of p38MAP kinase immunoprecipitated from CT6 cells was assayed by a kinase cascade involving Hsp27 kinase
(which is similar, if not identical to, MAPKAP kinase-2 (51)) and its
substrate (41). A substantial elevation in Hsp27 phosphorylation was
observed with p38MAP kinase immunoprecipitates from cytokine-treated
cells (Fig. 2a). Kinetic studies showed maximal activation by IL-7 was delayed when compared with IL-2 (Fig.
2b), although this has not been apparent in all experiments. TNF-
Preincubation (15 min) of CT6
cells (Fig. 3a) with the specific p38MAP
kinase inhibitor, SB203580, equally inhibited proliferation induced by
either IL-2 or IL-7 (IC50 ~3 µM). A similar
IC50 is observed for inhibition of TNF-
The effect of SB203580 on T cell proliferation led us to
question how closely this correlated with inhibition of one known function of p38MAP kinase. MAPKAP kinase-2 is phosphorylated and activated by p38MAP kinase in a number of cell types (41, 51), and this
is inhibited by SB203580 (53). As expected MAPKAP kinase-2 was
activated by IL-2 (Fig. 4a) in a
dose-dependent manner as judged by assays of the enzyme
immunoprecipitated from CT6 cells. Activity was maximal at 20 ng/ml
IL-2; the proliferative response of the cells displayed a similar dose
dependence (not shown). The activation of the enzyme was inhibited by
SB203580 (Fig. 4b) in the concentration range 0.1-1
µM, in agreement with the in vitro inhibition
of p38MAP kinase (53) and previous studies on MAPKAP kinase-2 (54).
There was no MAPKAP kinase-2 activity in control immunoprecipitations
with nonspecific antisera (not shown). In contrast, studies of ERK
phosphorylation by gel retardation assay showed that the IL-2-induced
phosphorylation was unaffected by 10 µM SB203580 (Fig.
4c), as was the SAPK/JNK activation measured by GST-ATF-2
phosphorylation in specific immunoprecipitates (Fig. 4d),
indicating the specificity of the compound.
DISCUSSION This study shows that the previously termed "stress-activated
kinases," p38MAP kinase and SAPK/JNK are activated in T cells by the
mitogenic cytokines IL-2 and IL-7. Moreover evidence is presented that
p38MAP kinase is involved in transducing these mitogenic responses.
This is in contrast to ERK, which has been shown previously not to be
necessary for T cell proliferation (14), opposing the paradigm in other
cells that it is ERK that is required for proliferative effects and
that p38MAP kinase is involved in stress responses.
The activation of p38MAP kinase by IL-2 and IL-7 is the first evidence
of the activation of this kinase in T cells. The recent identification
of highly specific pyrinidyl imidazole inhibitors of p38MAP kinase
allowed us to investigate its role in T cells responding to IL-2 or
IL-7. These inhibitors abrogate the synthesis of TNF- The nature of the signaling pathways leading to the activation of
p38MAP kinase by IL-2 and IL-7 is an open question. The activation of
MKK3/6 (55, 56), the G-proteins Rac and Cdc42 and p21-activated kinase
have been shown or implicated in the activation of p38MAP kinase in a
variety of cells (57, 58), however the response of these to IL-2 is
unknown. p21ras, which is activated by IL-2 (16, 17), has also
been suggested as a proximal activator for the kinase (59). However
IL-7 does not appear to stimulate the Shc/p21ras/ERK1/2 cascade
(14). As IL-2 and IL-7 both activate tyrosine kinases Jak1, Jak3, and
p56lck (3, 4, 6, 29, 32), it is possible that these may be
involved in initiating the signaling cascade to these kinases, and this
is currently being investigated. Moreover, the events distal to the
kinase are similarly unknown and warrant investigation. Our data have
shown that the induction of c-Myc was not affected and that the pathway
required for this event is still largely unknown. In other cells p38MAP
kinase has been implicated in the translational control of TNF
synthesis by unknown mechanisms (42). p38MAP kinase has also been shown
to phosphorylate and activate the transcription factors ATF-1 and CREB
(54), Elk-1 (60), CHOP (61), and ATF-2 (62). None of these are known to
be activated by IL-2, and although Elk-1 is involved in promoting fos
transcription induced by the cytokine, it is not required for
IL-2-driven cell proliferation (27).
The role played by SAPK/JNK in IL-2 and IL-7 function could not be
easily approached, as no specific inhibitor exists for this kinase.
However, IL-2 does induce the synthesis of c-Jun, in which SAPK/JNK has
been implicated (43). The activation of SAPK/JNK has been demonstrated
previously in T cells (44) in response to antibody cross-linking of CD3
and CD28. This involves a calcium signal, a requirement unique to T
lymphocytes. However, neither IL-2 nor IL-7 elevate intracellular
calcium (2), and thus the mechanism of activation of SAPK/JNK in T
cells by cytokines is distinct from that described previously. Nothing
is known of the response of MKK4 (63, 64) or MEKK (59), which are
proximal activators of SAPK/JNK, to IL-2 and IL-7. Furthermore despite its activation by some growth factors, e.g. epidermal growth
factor on HeLa cells (58), cholecystokinin on pancreatic cells (65), and both endothelin and thrombin on airway smooth muscle cells (66), no
role for SAPK/JNK in T cell mitogenesis has been defined.
In summary, we have shown that the previously termed stress-activated
kinases p38MAP kinase and SAPK/JNK are activated in T cells by the
mitogenic cytokines IL-2 and IL-7. Furthermore, using the specific
inhibitor SB203580 a previously undescribed role for p38MAP kinase in
mitogenesis has been observed. Moreover, p38MAP kinase is one of the
few elements of IL-2 and IL-7 signaling pathways that can be ascribed a
role in T cell proliferation. The involvement of these kinases in
inflammatory responses has identified them as likely therapeutic
targets. The observation that these kinases are also activated by T
cell mitogenic cytokines and that at least p38MAP kinase has a role in
transducing the proliferative response could have important
consequences for any pharmacological modulation of these enzymes.
FOOTNOTES REFERENCES
Volume 272, Number 23,
Issue of June 6, 1997
pp. 15023-15027
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
, IL-1, and lipopolysaccharide). Here we show that IL-2, and
another T cell growth factor, IL-7, activate both SAPK/JNK and p38MAP kinase. Furthermore, inhibition of p38MAP kinase activity with a
specific pyrinidyl imidazole inhibitor SB203580 that prevents activation of its downstream effector, MAPK-activating protein kinase-2, correlated with suppression of IL-2- and IL-7-driven T cell
proliferation. These data indicate that in T cells p38MAP kinase has a
role in transducing the mitogenic signal.
, 
, and
c subunits, the latter being shared with the receptors for IL-4,
IL-7, IL-9, and IL-15, other T cell growth factor cytokines (2).
-kinase (7,
8), and p70 S6 kinase (9-11). Furthermore, IL-2 activates ERK (12-14)
via a cascade of events involving the assembly of the
Shc·Grb-2·mSOS complex (15), the regulation of the GTPase
p21ras (16, 17), the activation of Raf-1 (18, 19), and by
inference MEK1/2. However, the contribution of all these events to the
proliferative activity of IL-2 is unclear. While the activation of Jak3
(4, 20, 21) and p70 S6 kinase (10, 22) are essential for the transduction of the mitogenic signal, a variety of studies have suggested that the activation of p56lck (6, 23), Syk (24), Jak1
(25), and the p21ras/ERK1/2 pathway are not required for the
proliferative response (14, 26, 27). Furthermore, while the activation
of Jak1 and Jak3 are common to the other T cell growth factors, IL-4
(28), IL-7 (29, 30), and IL-9 (31), activation of the other
IL-2-mediated events, with the exception of the IL-7-induced activation
of p56lck (32), has not been observed.
and IL-1 (39-43).
-glycerophosphate,
150 mM NaCl, 1% Triton T-X100, 10 mM NaF, 10%
glycerol, 2 mM EGTA, 2 mM
Na3VO4, 1 mM dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 1 µg/ml aprotinin, 1 µg/ml leupeptin, 1 µg/ml pepstatin. Lysates were centrifuged
12,000 × g for 10 min to precipitate debris. Kinases
were immunoprecipitated for 3 h at 4 °C with constant agitation
with specific antibody/protein-G-Sepharose (Pharmacia Biotech Inc.,
Milton Keynes, Bucks, UK). Immunoprecipitates were washed twice with
lysis buffer prior to Western immunoblotting and a further two times
with kinase assay buffer prior to kinase assays (25 mM
HEPES, pH 7.4, 25 mM -glycerophosphate, 25 mM MgCl2, 100 mM
Na3VO4, 2 mM dithiothreitol).
-32P]ATP
(Amersham International, Little Chalfont, Bucks, UK). After agitation
for 20 min at 25 °C, reactions were terminated by boiling with gel
sample buffer.
70 °C.
-32P]ATP. Following 20 min at 25 °C, reactions
were terminated by spotting the supernatants onto squares of P81 paper
and placing into 0.75% orthophosphoric acid. Following three washes in
acid and one in acetone, the squares were subjected to scintillation counting.
(Fig. 1b). No kinase activity was precipitated with
non-immune rabbit serum (Fig. 1, a and b), which confirmed the specificity of the assay.
Fig. 1.
IL-2 and IL-7 activate SAPK/JNK.
a, SAPK/JNK was immunoprecipitated from treated Kit-225
(a) or CT6 cells (b, c, d) and assayed using
GST-ATF-2 (a, c, d) or GST-Jun (b) as substrates. Cells were treated with IL-2 (20 ng/ml) or anisomycin (Ans, 25 ng/ml)
for the indicated times (a), IL-2, IL-7 (20 ng/ml), or TNF- (50 ng/ml) for 10 min (b), and IL-2 and IL-7 for 10 min at the indicated concentrations (c, d). The antisera
used for immunoprecipitation (IP) is indicated under the
corresponding lane (a, b).
[View Larger Version of this Image (42K GIF file)]
also activated p38MAP kinase as expected, although it should be
noted that CT6 cells possess only the p75 TNF receptor (p75 TNFR) (52),
while previous studies on the TNF- response have used cells that
also express the p55 TNFR. No kinase activity was precipitated by
non-immune rabbit serum (Fig. 2 a). Unlike SAPK/JNK, p38MAP
kinase has not been previously shown to be activated in T cells.
Fig. 2.
IL-2 and IL-7 activate p38MAP kinase.
a, Hsp27 phosphorylation in immunoprecipitates of p38MAP
kinase (containing purified inactivated Hsp27 kinase) from CT6 cells
treated with the indicated stimuli for 10 min and with cytokine for the
indicated time (b). The immunoprecipitating antisera are
indicated below each lane (a).
[View Larger Version of this Image (25K GIF file)]
production by
monocytes2 and for collagen-induced
platelet aggregation (45). We next examined the effect of this
inhibitor on primary T cells isolated from human blood (Fig. 3,
b and c). These were treated with anti-CD3 and
then induced to proliferate to IL-2 and IL-7. SB203580 inhibited the
proliferation over a concentration range similar to that observed in
the T cell lines. The compound was not toxic at the maximum concentrations used as judged by merocyanine staining in conjunction with fluorescence-activated cell sorter analysis (47) (not shown), nor
did it inhibit all responses to the cytokines, since expression of
c-Myc induced by IL-2 or IL-7 (14) was unaffected by 10 µM SB203580 (Fig. 3d).
Fig. 3.
SB203580 inhibits the proliferation of both
primary T cells and CT6 cells. a, inhibition of IL-2- and
IL-7-induced [3H]thymidine incorporation by the indicated
concentrations of SB203580 in CT6 cells and anti-CD3 (OKT-3, 35 ng/ml)-activated peripheral blood mononuclear cells (b, c).
d, Western immunoblot of c-Myc protein induced by IL-2 and
IL-7 in the presence or absence of 10 µM SB203580.
[View Larger Version of this Image (11K GIF file)]
Fig. 4.
IL-2 induction of MAPKAP kinase is sensitive
to SB203580. a, MAPKAP kinase-2 activity in
immunoprecipitates from CT6 cells treated with the indicated
concentrations of IL-2 for 20 min. b, effect of the
indicated concentrations of SB203580 on MAPKAP kinase-2
immunoprecipitated from CT6 cells treated with 20 ng/ml IL-2 for 20 min. c, Western immunoblot showing effect of SB203580 on
IL-2-induced (20 ng/ml for 10 min) phosphorylation of ERK in CT6 cells,
treated in the absence or presence of 10 µM SB203580 as
indicated, measured by electrophoretic mobility shift. d,
effect of SB203580 on IL-2-induced (20 ng/ml for 10 min) activation of
SAPK/JNK in CT6 cells in the absence or presence of 10 µM
SB203580 as indicated. The activity of the immunoprecipitated kinase
was measured using GST-ATF-2 as a substrate. The immunoprecipitating antisera are indicated above each lane (a).
[View Larger Version of this Image (17K GIF file)]
and IL-1 by
monocytes stimulated with lipopolysaccharide (42), and one, termed
SB203580, has been shown to be highly specific for p38MAP kinase (53).
The concentrations of drug that inhibited proliferation were
approximately one log higher than those required to inhibit the
activation of the immediate substrate MAPKAP kinase-2. This difference
in dose might be partly accounted for by the nature of the two
responses: one is a complex response and is measured 24 h after
stimulation, the other a single enzyme assayed after 20 min. The
possibility that SB203580 inhibits another protein kinase responsive to
IL-2 is unlikely, as it has no activity when tested on a large number
of other kinases at high concentration (53). However, the possible
existence of non-kinase targets cannot be absolutely discounted. These
results imply that p38MAP kinase has a novel role in mediating the
proliferative response of T cells to cytokines.
To whom correspondence should be addressed. Tel.: 0181-383-4444;
Fax: 0181-383-4499; E-mail: b.foxwell{at}cxwms.ac.uk.
1
The abbreviations used are: IL, interleukin;
ERK, extracellular signal-regulated kinase; MAP, mitogen-activated
protein; MAPK, MAP kinase; MAPKAP, MAPK-activating protein; SAPK,
stress-activated protein kinase; JNK, Jun-N-terminal kinase; TNF, tumor
necrosis factor; TNFR, TNF receptor; GST, glutathione
S-transferase.
2
L. M. Williams and B. M. J. Foxwell, unpublished
observations.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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A. Denys, I. A. Udalova, C. Smith, L. M. Williams, C. J. Ciesielski, J. Campbell, C. Andrews, D. Kwaitkowski, and B. M. J. Foxwell Evidence for a Dual Mechanism for IL-10 Suppression of TNF-{alpha} Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-{kappa}B in Primary Human Macrophages J. Immunol., May 15, 2002; 168(10): 4837 - 4845. [Abstract] [Full Text] [PDF]
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L. S. Chaturvedi, S. Koul, A. Sekhon, A. Bhandari, M. Menon, and H. K. Koul Oxalate Selectively Activates p38 Mitogen-activated Protein Kinase and c-Jun N-terminal Kinase Signal Transduction Pathways in Renal Epithelial Cells J. Biol. Chem., April 5, 2002; 277(15): 13321 - 13330. [Abstract] [Full Text] [PDF]
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 T ten Hove, B van den Blink, I Pronk, P Drillenburg, M P Peppelenbosch, and S J H van Deventer Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis Gut, April 1, 2002; 50(4): 507 - 512. [Abstract] [Full Text] [PDF]
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L. J. Appleman, A. A. F. L. van Puijenbroek, K. M. Shu, L. M. Nadler, and V. A. Boussiotis CD28 Costimulation Mediates Down-Regulation of p27kip1 and Cell Cycle Progression by Activation of the PI3K/PKB Signaling Pathway in Primary Human T Cells J. Immunol., March 15, 2002; 168(6): 2729 - 2736. [Abstract] [Full Text] [PDF]
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 P. Bostik, P. Wu, G. L. Dodd, F. Villinger, A. E. Mayne, V. Bostik, B. D. Grimm, D. Robinson, H.-J. Kung, and A. A. Ansari Identification of Protein Kinases Dysregulated in CD4+ T Cells in Pathogenic versus Apathogenic Simian Immunodeficiency Virus Infection J. Virol., December 1, 2001; 75(23): 11298 - 11306. [Abstract] [Full Text]
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A. R. Khaled, A. N. Moor, A. Li, K. Kim, D. K. Ferris, K. Muegge, R. J. Fisher, L. Fliegel, and S. K. Durum Trophic Factor Withdrawal: p38 Mitogen-Activated Protein Kinase Activates NHE1, Which Induces Intracellular Alkalinization Mol. Cell. Biol., November 15, 2001; 21(22): 7545 - 7557. [Abstract] [Full Text] [PDF]
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 W. Zhu, M. A. Brauchle, F. Di Padova, H. Gram, L. New, K. Ono, J. S. Downey, and J. Han Gene suppression by tristetraprolin and release by the p38 pathway Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L499 - L508. [Abstract] [Full Text] [PDF]
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N.-J. Chen, M.-W. Huang, and S.-L. Hsieh Enhanced Secretion of IFN-{{gamma}} by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine J. Immunol., January 1, 2001; 166(1): 270 - 276. [Abstract] [Full Text] [PDF]
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J. L. Cannons, Y. Choi, and T. H. Watts Role of TNF Receptor-Associated Factor 2 and p38 Mitogen-Activated Protein Kinase Activation During 4-1BB-Dependent Immune Response J. Immunol., December 1, 2000; 165(11): 6193 - 6204. [Abstract] [Full Text] [PDF]
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 H. T. Nguyen, R. M. Adam, S. H. Bride, J. M. Park, C. A. Peters, and M. R. Freeman Cyclic stretch activates p38 SAPK2-, ErbB2-, and AT1-dependent signaling in bladder smooth muscle cells Am J Physiol Cell Physiol, October 1, 2000; 279(4): C1155 - C1167. [Abstract] [Full Text] [PDF]
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R. Visconti, M. Gadina, M. Chiariello, E. H. Chen, L. F. Stancato, J. S. Gutkind, and J. J. O'Shea Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity Blood, September 1, 2000; 96(5): 1844 - 1852. [Abstract] [Full Text] [PDF]
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 S.-M. Chuang, G.-Y. Liou, and J.-L. Yang Activation of JNK, p38 and ERK mitogen-activated protein kinases by chromium(VI) is mediated through oxidative stress but does not affect cytotoxicity Carcinogenesis, August 1, 2000; 21(8): 1491 - 1500. [Abstract] [Full Text] [PDF]
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S. Zhang and M. H. Kaplan The p38 Mitogen-Activated Protein Kinase Is Required for IL-12-Induced IFN-{gamma} Expression J. Immunol., August 1, 2000; 165(3): 1374 - 1380. [Abstract] [Full Text] [PDF]
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K. M. Ardeshna, A. R. Pizzey, S. Devereux, and A. Khwaja The PI3 kinase, p38 SAP kinase, and NF-kappa B signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells Blood, August 1, 2000; 96(3): 1039 - 1046. [Abstract] [Full Text] [PDF]
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S.-M. Chuang, I-C. Wang, and J.-L. Yang Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium Carcinogenesis, July 1, 2000; 21(7): 1423 - 1432. [Abstract] [Full Text] [PDF]
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T.-K. Yu, E. G. Caudell, C. Smid, and E. A. Grimm IL-2 Activation of NK Cells: Involvement of MKK1/2/ERK But Not p38 Kinase Pathway J. Immunol., June 15, 2000; 164(12): 6244 - 6251. [Abstract] [Full Text] [PDF]
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 H. Kanasaki, K. Fukunaga, K. Takahashi, K. Miyazaki, and E. Miyamoto Involvement of p38 Mitogen-Activated Protein Kinase Activation in Bromocriptine-Induced Apoptosis in Rat Pituitary GH3 Cells Biol Reprod, June 1, 2000; 62(6): 1486 - 1494. [Abstract] [Full Text]
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P. G. del Arco, S. Martinez-Martinez, J. L. Maldonado, I. Ortega-Perez, and J. M. Redondo A Role for the p38 MAP Kinase Pathway in the Nuclear Shuttling of NFATp J. Biol. Chem., April 28, 2000; 275(18): 13872 - 13878. [Abstract] [Full Text] [PDF]
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E. Paine, R. Palmantier, S. K. Akiyama, K. Olden, and J. D. Roberts Arachidonic Acid Activates Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase 2 and Mediates Adhesion of a Human Breast Carcinoma Cell Line to Collagen Type IV through a p38 MAP Kinase-dependent Pathway J. Biol. Chem., April 6, 2000; 275(15): 11284 - 11290. [Abstract] [Full Text] [PDF]
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 N. Tripodis, S. Palmer, S. Phillips, S. Milne, S. Beck, and J. Ragoussis Construction of a High-Resolution 2.5-Mb Transcript Map of the Human 6p21.2-6p21.3 Region Immediately Centromeric of the Major Histocompatibility Complex Genome Res., April 1, 2000; 10(4): 454 - 472. [Abstract] [Full Text]
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F. V. Lali, A. E. Hunt, S. J. Turner, and B. M. J. Foxwell The Pyridinyl Imidazole Inhibitor SB203580 Blocks Phosphoinositide-dependent Protein Kinase Activity, Protein Kinase B Phosphorylation, and Retinoblastoma Hyperphosphorylation in Interleukin-2-stimulated T Cells Independently of p38 Mitogen-activated Protein Kinase J. Biol. Chem., March 15, 2000; 275(10): 7395 - 7402. [Abstract] [Full Text] [PDF]
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J. Harvey, N. G. McKay, K. S. Walker, J. Van der Kaay, C. P. Downes, and M. L. J. Ashford Essential Role of Phosphoinositide 3-Kinase in Leptin-induced KATP Channel Activation in the Rat CRI-G1 Insulinoma Cell Line J. Biol. Chem., February 18, 2000; 275(7): 4660 - 4669. [Abstract] [Full Text] [PDF]
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E. Fernandez Thymocyte development past the CD4+CD8+ stage requires an active p38 mitogen-activated protein kinase Blood, February 15, 2000; 95(4): 1356 - 1361. [Abstract] [Full Text] [PDF]
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T. Matsuguchi, K. Takagi, T. Musikacharoen, and Y. Yoshikai Gene expressions of lipopolysaccharide receptors, toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes Blood, February 15, 2000; 95(4): 1378 - 1385. [Abstract] [Full Text] [PDF]
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R. Yu, S. Mandlekar, W. Lei, W. E. Fahl, T.-H. Tan, and A.-N. T. Kong p38 Mitogen-activated Protein Kinase Negatively Regulates the Induction of Phase II Drug-metabolizing Enzymes That Detoxify Carcinogens J. Biol. Chem., January 28, 2000; 275(4): 2322 - 2327. [Abstract] [Full Text] [PDF]
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 S. A. Wadsworth, D. E. Cavender, S. A. Beers, P. Lalan, P. H. Schafer, E. A. Malloy, W. Wu, B. Fahmy, G. C. Olini, J. E. Davis, et al. RWJ 67657, a Potent, Orally Active Inhibitor of p38 Mitogen-Activated Protein Kinase J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 680 - 687. [Abstract] [Full Text]
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A. Mori, O. Kaminuma, K. Miyazawa, K. Ogawa, H. Okudaira, and K. Akiyama p38 Mitogen-Activated Protein Kinase Regulates Human T Cell IL-5 Synthesis J. Immunol., November 1, 1999; 163(9): 4763 - 4771. [Abstract] [Full Text] [PDF]
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S.-C. Hsu, M. A. Gavrilin, M.-H. Tsai, J. Han, and M.-Z. Lai p38 Mitogen-activated Protein Kinase Is Involved in Fas Ligand Expression J. Biol. Chem., September 3, 1999; 274(36): 25769 - 25776. [Abstract] [Full Text] [PDF]
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J. C. Hedges, M. A. Dechert, I. A. Yamboliev, J. L. Martin, E. Hickey, L. A. Weber, and W. T. Gerthoffer A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration J. Biol. Chem., August 20, 1999; 274(34): 24211 - 24219. [Abstract] [Full Text] [PDF]
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Y. Nagata and K. Todokoro Requirement of Activation of JNK and p38 for Environmental Stress-Induced Erythroid Differentiation and Apoptosis and of Inhibition of ERK for Apoptosis Blood, August 1, 1999; 94(3): 853 - 863. [Abstract] [Full Text] [PDF]
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M. Rolli, A. Kotlyarov, K. M. Sakamoto, M. Gaestel, and A. Neininger Stress-induced Stimulation of Early Growth Response Gene-1 by p38/Stress-activated Protein Kinase 2 Is Mediated by a cAMP-responsive Promoter Element in a MAPKAP Kinase 2-independent Manner J. Biol. Chem., July 9, 1999; 274(28): 19559 - 19564. [Abstract] [Full Text] [PDF]
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R. P. Singh, P. Dhawan, C. Golden, G. S. Kapoor, and K. D. Mehta One-way Cross-talk between p38MAPK and p42/44MAPK. INHIBITION OF p38MAPK INDUCES LOW DENSITY LIPOPROTEIN RECEPTOR EXPRESSION THROUGH ACTIVATION OF THE p42/44MAPK CASCADE J. Biol. Chem., July 9, 1999; 274(28): 19593 - 19600. [Abstract] [Full Text] [PDF]
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D. R. Jones, A. Gonzalez-Garcia, E. Diez, C. Martinez-A., A. C. Carrera, and I. Merida The Identification of Phosphatidylinositol 3,5-bisphosphate in T-lymphocytes and Its Regulation by Interleukin-2 J. Biol. Chem., June 25, 1999; 274(26): 18407 - 18413. [Abstract] [Full Text] [PDF]
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P. Maher p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation J. Biol. Chem., June 18, 1999; 274(25): 17491 - 17498. [Abstract] [Full Text] [PDF]
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A. Mortellaro, S. Songia, P. Gnocchi, M. Ferrari, C. Fornasiero, R. D'Alessio, A. Isetta, F. Colotta, and J. Golay New Immunosuppressive Drug PNU156804 Blocks IL-2-Dependent Proliferation and NF-{kappa}B and AP-1 Activation J. Immunol., June 15, 1999; 162(12): 7102 - 7109. [Abstract] [Full Text] [PDF]
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P. H. Schafer, S. A. Wadsworth, L. Wang, and J. J. Siekierka p38{alpha} Mitogen-Activated Protein Kinase Is Activated by CD28-Mediated Signaling and Is Required for IL-4 Production by Human CD4+CD45RO+ T Cells and Th2 Effector Cells J. Immunol., June 15, 1999; 162(12): 7110 - 7119. [Abstract] [Full Text] [PDF]
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A. Jaworowski, N. J. Wilson, E. Christy, R. Byrne, and J. A. Hamilton Roles of the Mitogen-activated Protein Kinase Family in Macrophage Responses to Colony Stimulating Factor-1 Addition and Withdrawal J. Biol. Chem., May 21, 1999; 274(21): 15127 - 15133. [Abstract] [Full Text] [PDF]
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Y. Nagata, F. Kiefer, T. Watanabe, and K. Todokoro Activation of Hematopoietic Progenitor Kinase-1 by Erythropoietin Blood, May 15, 1999; 93(10): 3347 - 3354. [Abstract] [Full Text] [PDF]
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J. Geginat, G. Bossi, J. R. Bender, and R. Pardi Anchorage Dependence of Mitogen-Induced G1 to S Transition in Primary T Lymphocytes J. Immunol., May 1, 1999; 162(9): 5085 - 5093. [Abstract] [Full Text] [PDF]
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N. Nath, H. Bian, E. F. Reed, and S. P. Chellappan HLA Class I-Mediated Induction of Cell Proliferation Involves Cyclin E-Mediated Inactivation of Rb Function and Induction of E2F Activity J. Immunol., May 1, 1999; 162(9): 5351 - 5358. [Abstract] [Full Text] [PDF]
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J. A. Gollob, C. P. Schnipper, E. A. Murphy, J. Ritz, and D. A. Frank The Functional Synergy Between IL-12 and IL-2 Involves p38 Mitogen-Activated Protein Kinase and Is Associated with the Augmentation of STAT Serine Phosphorylation J. Immunol., April 15, 1999; 162(8): 4472 - 4481. [Abstract] [Full Text] [PDF]
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M. Iacobelli, F. Rohwer, P. Shanahan, J. A. Quiroz, and K. L. McGuire IL-2-Mediated Cell Cycle Progression and Inhibition of Apoptosis Does Not Require NF-{kappa}B or Activating Protein-1 Activation in Primary Human T Cells J. Immunol., March 15, 1999; 162(6): 3308 - 3315. [Abstract] [Full Text] [PDF]
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A. E. Hunt, F. V. Lali, J. D. Lord, B. H. Nelson, T. Miyazaki, K. J. Tracey, and B. M. J. Foxwell Role of Interleukin (IL)-2 Receptor beta -Chain Subdomains and Shc in p38 Mitogen-activated Protein (MAP) Kinase and p54 MAP Kinase (Stress-activated Protein Kinase/c-Jun N-terminal Kinase) Activation. IL-2-DRIVEN PROLIFERATION IS INDEPENDENT OF p38 AND p54 MAP KINASE ACTIVATION J. Biol. Chem., March 12, 1999; 274(11): 7591 - 7597. [Abstract] [Full Text] [PDF]
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C. Lawson, M. Ainsworth, M. Yacoub, and M. Rose Ligation of ICAM-1 on Endothelial Cells Leads to Expression of VCAM-1 Via a Nuclear Factor-{kappa}B-Independent Mechanism J. Immunol., March 1, 1999; 162(5): 2990 - 2996. [Abstract] [Full Text] [PDF]
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M. Gadina, C. Sudarshan, and J. J. O'Shea IL-2, But Not IL-4 and Other Cytokines, Induces Phosphorylation of a 98-kDa Protein Associated with SHP-2, Phosphatidylinositol 3'-Kinase, and Grb2 J. Immunol., February 15, 1999; 162(4): 2081 - 2086. [Abstract] [Full Text] [PDF]
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O. Rausch and C. J. Marshall Cooperation of p38 and Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase Pathways during Granulocyte Colony-stimulating Factor-induced Hemopoietic Cell Proliferation J. Biol. Chem., February 12, 1999; 274(7): 4096 - 4105. [Abstract] [Full Text] [PDF]
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N. Douziech, E. Calvo, Z. Coulombe, G. Muradia, J. Bastien, R. A. Aubin, A. Lajas, and J. Morisset Inhibitory and Stimulatory Effects of Somatostatin on Two Human Pancreatic Cancer Cell Lines: A Primary Role for Tyrosine Phosphatase SHP-1 Endocrinology, February 1, 1999; 140(2): 765 - 777. [Abstract] [Full Text]
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P. H. Schafer, L. Wang, S. A. Wadsworth, J. E. Davis, and J. J. Siekierka T Cell Activation Signals Up-Regulate p38 Mitogen-Activated Protein Kinase Activity and Induce TNF-{alpha} Production in a Manner Distinct from LPS Activation of Monocytes J. Immunol., January 15, 1999; 162(2): 659 - 668. [Abstract] [Full Text] [PDF]
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J. L. E. Dean, M. Brook, A. R. Clark, and J. Saklatvala p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes J. Biol. Chem., January 1, 1999; 274(1): 264 - 269. [Abstract] [Full Text] [PDF]
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 C. WIDMANN, S. GIBSON, M. B. JARPE, and G. L. JOHNSON Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module From Yeast to Human Physiol Rev, January 1, 1999; 79(1): 143 - 180. [Abstract] [Full Text] [PDF]
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J.-J. Hung, T.-J. Cheng, Y.-K. Lai, and M. D.-T. Chang Differential Activation of p38 Mitogen-activated Protein Kinase and Extracellular Signal-regulated Protein Kinases Confers Cadmium-induced HSP70 Expression in 9L Rat Brain Tumor Cells J. Biol. Chem., November 27, 1998; 273(48): 31924 - 31931. [Abstract] [Full Text] [PDF]
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A. Craxton, G. Shu, J. D. Graves, J. Saklatvala, E. G. Krebs, and E. A. Clark p38 MAPK Is Required for CD40-Induced Gene Expression and Proliferation in B Lymphocytes J. Immunol., October 1, 1998; 161(7): 3225 - 3236. [Abstract] [Full Text] [PDF]
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Y. Nagata, N. Takahashi, R. J. Davis, and K. Todokoro Activation of p38 MAP Kinase and JNK But Not ERK Is Required for Erythropoietin-Induced Erythroid Differentiation Blood, September 15, 1998; 92(6): 1859 - 1869. [Abstract] [Full Text] [PDF]
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C. S. T. Hii, Z. H. Huang, A. Bilney, M. Costabile, A. W. Murray, D. A. Rathjen, C. J Der, and A. Ferrante Stimulation of p38 Phosphorylation and Activity by Arachidonic Acid in HeLa Cells, HL60 Promyelocytic Leukemic Cells, and Human Neutrophils. EVIDENCE FOR CELL TYPE-SPECIFIC ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., July 24, 1998; 273(30): 19277 - 19282. [Abstract] [Full Text] [PDF]
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M. Ushio-Fukai, R. W. Alexander, M. Akers, and K. K. Griendling p38 Mitogen-activated Protein Kinase Is a Critical Component of the Redox-sensitive Signaling Pathways Activated by Angiotensin II. ROLE IN VASCULAR SMOOTH MUSCLE CELL HYPERTROPHY J. Biol. Chem., June 12, 1998; 273(24): 15022 - 15029. [Abstract] [Full Text] [PDF]
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H.-L. Cheng and E. L. Feldman Bidirectional Regulation of p38 Kinase and c-Jun N-terminal Protein Kinase by Insulin-like Growth Factor-I J. Biol. Chem., June 5, 1998; 273(23): 14560 - 14565. [Abstract] [Full Text] [PDF]
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A. Hoffmeyer, A. Avots, E. Flory, C. K. Weber, E. Serfling, and U. R. Rapp The GABP-responsive Element of the Interleukin-2 Enhancer Is Regulated by JNK/SAPK-activating Pathways in T Lymphocytes J. Biol. Chem., April 24, 1998; 273(17): 10112 - 10119. [Abstract] [Full Text] [PDF]
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H. Enslen, J. Raingeaud, and R. J. Davis Selective Activation of p38 Mitogen-activated Protein (MAP) Kinase Isoforms by the MAP Kinase Kinases MKK3 and MKK6 J. Biol. Chem., January 16, 1998; 273(3): 1741 - 1748. [Abstract] [Full Text] [PDF]
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K.-D. Chen, L.-Y. Chen, H.-L. Huang, C.-H. Lieu, Y.-N. Chang, M. D.-T. Chang, and Y.-K. Lai Involvement of p38 Mitogen-activated Protein Kinase Signaling Pathway in the Rapid Induction of the 78-kDa Glucose-regulated Protein in 9L Rat Brain Tumor Cells J. Biol. Chem., January 9, 1998; 273(2): 749 - 755. [Abstract] [Full Text] [PDF]
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M. Gadina, C. Sudarshan, R. Visconti, Y.-J. Zhou, H. Gu, B. G. Neel, and J. J. O'Shea The Docking Molecule Gab2 Is Induced by Lymphocyte Activation and Is Involved in Signaling by Interleukin-2 and Interleukin-15 but Not Other Common gamma Chain-using Cytokines J. Biol. Chem., August 25, 2000; 275(35): 26959 - 26966. [Abstract] [Full Text] [PDF]
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S. J. Coniglio, T.-S. Jou, and M. Symons Rac1 Protects Epithelial Cells against Anoikis J. Biol. Chem., July 20, 2001; 276(30): 28113 - 28120. [Abstract] [Full Text] [PDF]
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Y. Abe, S. Matsumoto, K. Kito, and N. Ueda Cloning and Expression of a Novel MAPKK-like Protein Kinase, Lymphokine-activated Killer T-cell-originated Protein Kinase, Specifically Expressed in the Testis and Activated Lymphoid Cells J. Biol. Chem., July 7, 2000; 275(28): 21525 - 21531. [Abstract] [Full Text] [PDF]
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