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Department of Physiology and Biophysics, University of Iowa (B.P.C., J.E.P.), Iowa City, Iowa 52242; and the Department of Molecular and Cellular Biology, Rockefeller University (C.M.H.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Jeffrey E. Pessin, Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242-1109. E-mail: Jeffrey-Pessin{at}UIOWA.EDU
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, it has become apparent that a second phosphorylation event is
required for maximal STAT-mediated DNA transcriptional activity. For
example, serine phosphorylation of STAT1
and STAT3 enhances
cytokine-stimulated transcriptional activation, as determined by
in vitro transcription, in vivo reporter gene
assays, and STAT-dependent mitogenesis (25, 26, 27). As the
carboxyl-terminal serine residue (727) is located within a consensus
mitogen-activated protein (MAP) kinase phosphorylation acceptor site,
it has been suggested that MAP kinase is responsible for the
cytokine-stimulated serine phosphorylation of the STAT proteins (25, 28). In this regard, we have previously reported that insulin
stimulation results in the selective serine phosphorylation of STAT3
without any detectable tyrosine phosphorylation (29). As the insulin
signaling pathway leading to STAT3 serine phosphorylation is distinct
from the cytokine/growth factor stimulation of STAT tyrosine
phosphorylation, we have taken advantage of this system to examine the
molecular events responsible for STAT3 serine phosphorylation. In the
present report, we have determined that insulin stimulation results in
the serine phosphorylation of STAT3 on serine 727. This occurs through
a Ras-dependent pathway leading to the activation of MEK. However,
neither the established downstream kinase (ERK) nor the activation of
the two other mammalian MAP kinases (JNK or p38) is required. These
data demonstrate the presence of a novel MEK-dependent MAP kinase that
is responsible for the insulin-stimulated serine phosphorylation of
STAT3.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell culture
Chinese hamster ovary cells expressing high levels of the human
insulin receptor (CHO/IR) were isolated and cultured in MEM
supplemented with 10% FBS, streptomycin, penicillin, and glutamine, as
described previously (30). The cells were serum starved for 3–4 h
before the addition of 100 nM insulin, 100 U/ml
interleukin-6 (IL-6), 50 µg/ml anisomycin, or 600 mM
sorbitol for various times (0–15 min) as indicated in the figure
legends. In some experiments, the cells were pretreated for 1 h
with 1% dimethylsulfoxide or with 100 µM PD98059 in 1%
dimethylsulfoxide. Stimulation was terminated by two washes in ice-cold
PBS, pH 7.4, and removal of excess liquid by aspiration, and cells were
snap-frozen by the addition of liquid nitrogen to the tissue culture
plates. Frozen cells were stored at -80 C until harvested.
Whole cell detergent lysates
CHO/IR cells were extracted in ice-cold lysis buffer A (50
mM HEPES, 1% Triton X-100, 2.5 mM EDTA, 100
mM NaF, and 10 mM
Na4P2O7, pH 7.8) containing 1
mM phenylmethylsulfonylfluoride, 2 mM
Na3VO4, 1 µg/ml aprotinin, 10
µM leupeptin, and 1 µM pepstatin A by
rotation for 10 min at 4 C. Insoluble material was separated from the
soluble extract by microcentrifugation for 10 min at 4 C. Protein
concentration was determined by Bradford assay (Bio-Rad, Richmond,
CA).
Immunoprecipitation and Western blot analysis
Cells were solubilized on ice in 500 µl immunoprecipitation
buffer (150 mM NaCl, 1% Nonidet P-40, 0.5% deoxycholate,
0.1% SDS, 50 mM Tris, 10 mM
Na4P2O7, 100 mM NaF, 2
mM phenylmethylsulfonylfluoride, 2 mM
Na3VO4, 2 µM pepstatin A, 1
µg/ml aprotinin, and 10 µM leupeptin) by rotation at 4
C for 10 min, and the insoluble material was removed by
microcentrifugation at 4 C for 10 min. The solubilized cell lysate was
incubated with 1 µg STAT3 polyclonal antibody (Santa Cruz). Whole
cell lysates (75 µg protein) or STAT3 immunoprecipitates were
subjected to SDS-PAGE and transferred to polyvinylidene difluoride
filters. In experiments that examined protein phosphorylation by a
retarded electrophoretic mobility on SDS-PAGE, 7.5% acrylamide gels
were used to examine changes in STAT3, and 10% acrylamide gels were
used to study ERK. The polyvinylidene difluoride membranes were
subjected to Western blot analysis according to the manufacturer’s
recommendations. Immunoreactive proteins were visualized by enhanced
chemiluminescence (Amersham, Arlington Heights, IL) according to the
manufacturer’s instructions.
In vitro kinase assays
In vitro kinase assays were performed as previously
described (31, 32). Briefly, ERK activity was determined in ERK
immunoprecipitates using myelin basic protein as substrate. p38 kinase
activity was determined in p38 immunoprecipitates using activating
transcription factor-2 as substrate. JNK activity was determined by
incubation of the cell extracts with 10 µg
glutathione-S-transferase-c-Jun-(1–79) agarose for 4 h
at 4 C, followed by the addition of [
-32P]ATP. All
three kinase reactions were terminated by the addition of Laemmli
sample buffer, boiling for 5 min, and centrifugation. The
32P-labeled substrates were separated by SDS-PAGE and,
after Coomassie staining of the gel, were visualized by
autoradiography.
Transfection by electroporation
The CHO/IR cells were suspended in 500 µl PBS with a total of
40 µg empty vector, the mammalian expression vector containing the
wild-type and S727A STAT3 cDNAs. The cells were then electroporated at
340 V and 960 µF and plated in MEM containing 10% serum. Cell
debris was removed by replacing medium with fresh medium 12 and 30
h later. Forty-eight hours later, the transfected cells were serum
starved for 2–3 h and either untreated or stimulated as described
above.
Generation of S727A Flag-STAT3 cDNA
The murine S727A Flag STAT3 was generated by AccI and
NcoI digestion of a PCR-amplified 380-bp fragment containing
the serine to alanine mutation from S727A STAT3 and subcloning it into
wild-type Flag-STAT3 that had been partially digested with
AccI and NcoI. The point mutation was confirmed
by sequencing.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. As serine
phosphorylation is accompanied by a reduction in SDS-polyacrylamide gel
electrophoretic mobility, immunoblotting with the Flag antibody is a
convenient assay to monitor serine phosphorylation of the expressed
STAT3 protein (29). In mock-transfected cells, we did not detect any
immunoreactive proteins, demonstrating the specificity of the Flag
antibody (Fig. 1B, lane 1). However, transfection with either the
wild-type Flag-STAT3 or S727A Flag-STAT3 cDNAs demonstrated the
expression of the STAT3 proteins (Fig. 1B, lanes 2 and 4). As
previously observed for the endogenous STAT3 protein, insulin
stimulation resulted in a marked reduction in electrophoretic mobility
that directly resulted from serine phosphorylation (Fig. 1B, lane 3).
In contrast, insulin stimulation of cells expressing the S727A
Flag-STAT3 failed to display any insulin-stimulated gel shift (Fig. 2B, lane 5). These data demonstrate that
serine-727 is a site of insulin-stimulated STAT3 phosphorylation.
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). Insulin treatment resulted in a time-dependent
serine phosphorylation of the endogenous STAT3 that was initially
observed by approximately 2 min (Fig. 2A, lanes 1–3). The maximal
decrease in electrophoretic mobility occurred by 5 min and remained
relatively persistent for up to 30 min (Fig. 2A, lanes 4–6). In
contrast, cytokine stimulation resulted in a much slower time course of
STAT3 serine phosphorylation, which was not apparent until 15 min after
IL-6 treatment (Fig. 2B, lanes 1–6). Based upon the temporal
separation of these events, the cells were incubated with insulin and
IL-6 separately and in combination (Fig. 2C). Insulin treatment for 5
min resulted in the characteristic gel shift of the STAT3 proteins
isolated by STAT3 immunoprecipitation (Fig. 2C, lanes 1 and 2). As
expected, IL-6 treatment for 5 min had no significant effect on STAT3
mobility (Fig 2C, lane 3), whereas incubation of the cells for 5 min
with insulin and IL-6 resulted in a STAT3 gel shift identical to that
seen after insulin treatment alone (Fig. 2C, lane 4). In comparison,
there was no detectable tyrosine phosphorylation of STAT3 in either the
unstimulated or insulin-stimulated cells (Fig. 2D, lanes 1 and 2).
Although IL-6 induced the tyrosine phosphorylation of STAT3, there was
little effect on the extent of serine phosphorylation (Fig. 2D, lane
3). In contrast, treatment of the cells with both insulin and IL-6
resulted in both a gel shift and tyrosine phosphorylation of STAT3
(Fig. 2D, lane 4). These data demonstrate that insulin stimulation in
concert with IL-6 stimulation induces both tyrosine and serine
phosphorylation of STAT3.
ERK activation correlates with STAT3 serine phosphorylation
The selective ability of insulin to induce only the serine
phosphorylation of STAT3 allowed us to dissect this pathway without any
potential complicating effects due to STAT3 tyrosine phosphorylation by
JAK activation. In addition, serine-727 is located within a consensus
acceptor site for members of the MAP kinase family of proline-directed
serine/threonine kinases (PXS/TP) (33). Therefore, we next determined
the relative contributions of the three known mammalian MAP kinases
(ERK, JNK, and p38) to induce STAT3 serine phosphorylation (Fig. 3). The protein synthesis inhibitor
anisomycin was a relatively poor activator of ERK with essentially
identical levels of ERK activity compared with those of the
unstimulated cells (Fig. 3A, lanes 3, 4, and 7). In contrast, insulin
was a very potent activator of ERK (Fig. 3A, lanes 1 and 2). Similarly,
osmotic shock also induced ERK activation, albeit with a slower time
course and to a lesser extent than insulin (Fig. 3A, lanes 5 and 6). In
contrast, anisomycin and osmotic shock were strong activators of p38
MAP kinase activity, whereas insulin had very little effect on p38 MAP
kinase (Fig. 3B, lanes 1–7). In addition, anisomycin and osmotic shock
treatment resulted in JNK activation, whereas insulin was a relatively
poor activator of this MAP kinase (Fig. 3C, lanes 1–7). Under
identical conditions, anisomycin was completely unable to induce the
serine phosphorylation of STAT3 (Fig. 3D, lanes 1 and 2). However, both
insulin and osmotic shock treatment resulted in STAT3 serine
phosphorylation in proportion to the extent of ERK activation (Fig. 3D, lanes 5 and 6). Together, these data demonstrate that the decrease in
STAT3 electrophoretic mobility correlates with ERK activation, whereas
there was no correlation with either JNK or p38 MAP kinase
activity.
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). In each case, we examined ERK
activation as a downstream readout, which was assessed by its
characteristic gel shift due to threonine and tyrosine phosphorylation.
In mock-transfected cells, insulin induced a typical gel shift of ERK2,
which correlates with ERK phosphorylation and activation (Fig. 4A, lanes 1–3). In contrast, expression of a dominant-interfering Ras
mutant (N17Ras) decreased the insulin-stimulated ERK gel shift,
consistent with the requirement for Ras function (Fig. 4A, lanes 4–6)
(34). Similar to the effect on ERK, expression of N17 Ras decreased the
insulin-stimulated serine phosphorylation of STAT3 (Fig. 4A, lanes
7–12).
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, lanes 1–6). Similarly, the MEK
inhibitor completely prevented STAT3 serine phosphorylation after 5 min
of insulin stimulation. A reduction in the extent of STAT3 gel shift
was seen after 15 min (Fig. 4B, lanes 7–12), consistent with the low
level of active ERK detected in this experiment.
To assess the contribution of ERK in this pathway, we next examined the
effect of the phosphothreonine and phosphotyrosine dual specificity
phosphatase MKP-1 on insulin-mediated serine phosphorylation of STAT3.
MKP-1 has been shown to dephosphorylate all known members of the MAP
kinase family of protein kinases (ERK, p38, and JNK) (36, 37, 38, 39). However,
for these studies, only dephosphorylation of ERK2 is relevant, as it is
the principle ERK found in CHO cells (40) and is the predominant MAP
kinase activated by insulin (Fig. 2, A–C). As expected, control
vector-transfected cells displayed an insulin stimulation of ERK
activation that was fully inhibited by expression of MKP-1 (Fig. 4C, lanes 1–6). Surprisingly, however, expression of MKP-1 had no effect
on the ability of insulin to induce the serine phosphorylation of STAT3
(Fig. 4C, lanes 7–12). Together, these data demonstrate that the
insulin-stimulated serine phosphorylation of STAT3 occurs at least in
part by a MEK-dependent, but ERK-independent, mechanism.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although several functional regions of the STAT3 protein have been well characterized, such as the DNA-binding domain (amino acids 400–500), the SH2, and a putative SH3 domain (between amino acids 510 and 700) and tyrosine phosphorylation acceptor site (amino acid 705), other important regulator regions remain poorly understood (7, 8, 11). Recently, the serine phosphorylation of amino acid 727 has been reported to potentiate STAT transcriptional activity both in vivo and in vitro (25, 26, 27, 41). Although serine phosphorylation alone is not sufficient to support nuclear translocation, it has been observed to modulate the dimerization of the STAT proteins induced by tyrosine phosphorylation (42, 43). Thus, it has been proposed that serine phosphorylation serves to fine-tune the degree of transcriptional activation and perhaps the specificity of target cis-DNA elements by modulating the relative proportions of homo- vs. heterodimerization of the STAT proteins. However, it has been difficult to determine the pathways leading to STAT serine phosphorylation due to the combination of both JAK tyrosine kinase and serine/threonine kinase activation by cytokine receptors (28). In this regard, we have recently observed that insulin stimulation results in a selective serine phosphorylation of STAT3 without any effect on tyrosine phosphorylation (29). The lack of insulin-stimulated tyrosine phosphorylation is consistent with previous studies demonstrating the inability of insulin to activate JAK (20, 44, 45). We, therefore, exploited this system to identify the site of insulin-stimulated STAT3 phosphorylation and to characterize the signaling pathways involved.
In this study, we demonstrated that insulin induces the phosphorylation
of STAT3 on serine-727, which is in the STAT consensus sequence and is
phosphorylated after activation by several cytokines, including
interferon-, interferon-, and IL-6 (25, 26, 27). In addition, the
tyrosine phosphorylation and serine phosphorylation of STAT3 are two
separate independent events. That is, insulin induces a selective
serine phosphorylation of STAT3, whereas initial stimulation by IL-6
results in the selective tyrosine phosphorylation of STAT3.
Furthermore, a combination of both insulin and IL-6 induces a more
rapid appearance of the dual serine- and tyrosine-phosphorylated state.
These data demonstrate that serine phosphorylation of STAT3 is not
dependent upon prior tyrosine phosphorylation or vice
versa.
The STAT3 serine phosphorylation site is located within a canonical MAP kinase phosphorylation motif (PXS/TP), and based upon in vitro phosphorylation, it was proposed that the ERK family of MAP kinases was responsible (25). However, other members of the MAP kinase family (JNK and p38) are also proline-directed kinases that have a significant degree in substrate overlap with ERK (46). To determine which of these kinase pathways is required for STAT3 serine phosphorylation, we initially examined the abilities of various agonists to stimulate STAT3 serine phosphorylation. In these cells, anisomycin was an activator of JNK and p38, but did not result in any appreciable activation of the ERK pathway. In contrast, insulin was a strong activator of ERK, but was a poor stimulant for both JNK and p38. On the other hand, osmotic shock was capable of activating all three MAP kinase pathways (ERK, JNK, and p38). The fact that only insulin and osmotic shock were capable of inducing STAT3 serine phosphorylation clearly excludes both the JNK and p38 MAP kinase pathways in this event. Furthermore, expression of dominant-interfering Ras inhibited the insulin stimulation of STAT3 serine phosphorylation, directly implicating the Ras/RAF/MEK/ERK pathway.
Surprisingly, however, inhibition of ERK activation by expression of MKP-1 had no effect on STAT3 serine phosphorylation. This was in contrast to inhibition of MEK activation, which markedly reduced the ability of insulin to stimulate STAT3 serine phosphorylation. Together, these data indicate the presence of a novel MEK-dependent kinase that lies in a pathway leading to STAT3 serine phosphorylation. This observation is consistent with recent studies, suggesting the presence of a distinct serine/threonine kinase downstream of MEK that is responsible for the feedback phosphorylation of SOS and termination of the Ras activation signal (38, 47).
It is also interesting to note that the carboxyl-terminal domain
encompassing serine-727 of STAT3 is highly conserved in four of the
other STAT isoforms (STAT1, -4, -5a, and -6). However, insulin
stimulation results only in the serine phosphorylation of STAT3 and not
these other isoforms (29). Whether the STAT3-specific serine
phosphorylation results from a unique specificity of this novel kinase
or differential compartmentalization of the STAT proteins with the
MEK-dependent kinase remains to be determined.
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Acknowledgments |
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Footnotes |
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2 Recipient of a postdoctoral fellowship award from the Juvenile
Diabetes Foundation International.
Received April 1, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
Proc Natl Acad Sci USA 89:7836–7839. Science 261:1744–1746 of tyrosine phosphorylated DNA binding proteins
in mouse liver nuclei. Science 261:1733–1736 and interferon. Mol Cell Biol 11:182–191 regulated DNA binding factor.
EMBO J 10:927–932[Medline]
and interferon .
Proc Natl Acad Sci USA 93:7673–7678- and interferon ß-stimulated gene expression through STAT
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