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Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
Address all correspondence and requests for reprints to: Dr. Naohito Aoki, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: naoki{at}agr
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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PRL exhibits its activity through its cognate receptor and the activation of intracellular signaling molecules such as the Janus kinase 2 (JAK2) and signal transducers and activators of transcription 5 (STAT5). The PRL receptor, belonging to the hemopoietin receptor superfamily (4), does not possess intrinsic tyrosine kinase activity, but is constitutively associated with the cytoplasmic tyrosine kinase JAK2 (5, 6, 7). Upon ligand binding, the PRL receptor dimerizes, and JAK2 is activated through autophosphorylation on tyrosine residue (7). JAK2 then phosphorylates not only the PRL receptor, but also the transcription factors STAT5a and STAT5b, which then form homodimers, translocate to the nucleus, and specifically bind to the promoter regions of target genes, thus activating transcription (8, 9).
It has been demonstrated that STAT5 undergoes a rapid and transient activation and deactivation cycle through tyrosine phosphorylation upon cytokine stimulation (10). Because tyrosine phosphorylation is essential for PRL signaling, PTPs are believed to attenuate or block it and play a negative role. Although recent publications have shown that SH2-containing protein tyrosine phosphatase-2 (SHP-2) is involved in ß-casein promoter activation in a positive manner (11, 12), dephosphorylation of the activated JAK2 and STAT5 through the PRL receptor and the involvement of the PTPs in a negative regulation remains to be elucidated.
More recently, we demonstrated that cytosolic PTP1B dephosphorylated and deactivated STAT5a and STAT5b in transfected COS-7 cells as well as in mammary epithelial COMMA-1D cells, thereby negatively regulating the PRL-mediated signaling pathway (13). As PTP1B and structurally highly related TC-PTP comprises a subfamily of cytosolic PTPs and TC-PTP was also shown to be expressed in mammary gland and mammary epithelial cells (14), in this study we examined the involvement of TC-PTP in the PRL-mediated signaling pathway. The data demonstrated that TC-PTP was also a potential negative regulator of PRL-mediated signal transduction by specifically dephosphorylating and deactivating STAT5 in nucleus. Our previous and current studies suggest that STAT5 might be cooperatively regulated in cytosol as well as in nucleus in mammary epithelial cells.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). The cDNA
sequence of only a C-terminally truncated form of TC-PTP with a
molecular mass of 45 kDa has been available for mouse species
(15, 16), whereas the protein sequence of the 48-kDa form
of TC-PTP has been reported previously (17). The mouse
45-kDa TC-PTP was cloned by RT-PCR amplification, hemagglutinin (HA)
epitope-tagged at its N-terminus, and examined for dephosphorylation of
PRL-activated STAT5a and STAT5b.
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, A and B), whereas more than 90% of the proteins were dephosphorylated
by PTP1B under the same conditions (13). Dephosphorylation
of STAT5a and STAT5b was not observed when the cells were cotransfected
with catalytically inactive Cys/Ser or Asp/Ala mutant of TC-PTP,
suggesting that phosphatase activity of TC-PTP is essential for the
dephosphorylation of STAT5. Comparable expression of TC-PTP wild type
and mutants was confirmed by immunoblotting with anti-HA antibody (Fig. 2, lower panels).
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, the
tyrosine phosphorylation level of STAT5a was reduced to approximately
50% by 1 µg GST-TC-PTP wild type, and incubation with 10 µg of the
fusion protein resulted in complete dephosphorylation of STAT5a
(upper panels). In a similar manner, STAT5b was
dephosphorylated by GST-TC-PTP wild type (lower panels). In
both cases such dephosphorylation of STAT5 proteins by TC-PTP was
indistinguishable from that by PTP1B (13), suggesting that
TC-PTP and PTP1B can dephosphorylate STAT5 in a similar manner in
vitro. Incubation of the immune complexes with empty GST and GST
fused to catalytically inactive mutants of TC-PTP as well as GST-SHP-1
and -HSCF (data not shown) resulted in no reduction in tyrosine
phosphorylation level of STAT5a and STAT5b.
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, in the absence of vanadate in cell
lysates, tyrosine-phosphorylated 97-kDa protein was
coimmunoprecipitated with Asp/Ala and, to a lesser extent, with the
Cys/Ser mutant of TC-PTP, whereas such a tyrosine-phosphorylated band
was scarcely detected in the immune complex of TC-PTP wild type
(left panels). The membranes were stripped and reprobed with
anti-STAT5 antibody. The tyrosine-phosphorylated 97-kDa band was
demonstrated to be STAT5a and STAT5b by immunoblotting. On the other
hand, in the absence of vanadate in cell lysates, such a
tyrosine-phosphorylated 97-kDa band was not detected (right
panels). Interestingly, STAT5 was also slightly present in the
immune complexes of TC-PTP wild type regardless of the presence or
absence of vanadate as well as in those of TC-PTP mutants in the
presence of vanadate, suggesting some contribution of
phosphotyrosine-independent interaction of TC-PTP with STAT5, as
observed for PTP1B (13).
TC-PTP Is a Potential Negative Regulator in PRL Receptor-Mediated
Signaling in Mammary Epithelial Cells
To demonstrate more physiological relevance of
TC-PTP in PRL-mediated signaling, TC-PTP was introduced into mammary
epithelial COMMA-1D cells by a retroviral infection system. TC-PTP cDNA
was ligated into a retroviral vector and introduced into mammary
epithelial cells. Cells were selected in G418-supplemented cell culture
medium and then directly used for subsequent experiments. The
polyclonal cells expressing PTP1B wild type were also included as a
control. Nearly the same amounts of HA-tagged TC-PTP and HA-tagged
PTP1B were expressed in the cells (Fig. 4A).
Cells were serum-starved and lysed at the various time points indicated
after PRL stimulation. Endogenous STAT5 was immunoprecipitated,
followed by immunoblotting with antiphosphotyrosine antibody. Five
minutes after PRL stimulation, tyrosine phosphorylation of STAT5 did
not differ in mock and TC-PTP infectants, whereas only faint signal was
detected in PTP1B wild type-expressing cells at the same time point
(Fig. 4, B and C). The phosphorylation level of STAT5 in TC-PTP wild
type-expressing cells was significantly less than that in mock
transfectants or cells expressing TC-PTP mutants 10 min after PRL
stimulation, and this became more obvious after 30 min. More than 90%
of STAT5 was dephosphorylated after 40-min PRL stimulation in TC-PTP
wild type-expressing cells, which was nearly the same as in
PTP1B-expressing cells at the same time point. On the other hand, in
the cells expressing inactive Cys/Ser and Asp/Ala mutants of TC-PTP,
the phosphorylation level of STAT5 was not significantly different from
that in mock infectants at all time points examined. Phosphorylation of
JAK2 upon PRL stimulation was not affected by overexpressing TC-PTP
wild type as well as catalytically inactive forms of TC-PTP (Fig. 4D).
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, ß-casein gene expression was largely suppressed in the cells
expressing TC-PTP wild type, which was comparable in the cells
expressing PTP1B wild type. Surprisingly, overexpression of Cys/Ser as
well as Asp/Ala mutants of TC-PTP also suppressed ß-casein gene
expression, and the expression level in Asp/Ala mutant-expressing cells
was less and indistinguishable from that in TC-PTP wild type-expressing
cells, whereas overexpression of PTP1B mutants exhibited apparently no
effect on ß-casein gene expression (13). This suggests
that whereas TC-PTP wild type has the capacity to dephosphorylate
STAT5, the TC-PTP mutants would bind to the phosphotyrosine on the
STAT5 through mutated catalytic domains, thus competing with the SH2
domain of the STAT5 and interfering with binding to ß-casein gene
promoter sequence.
These results were further confirmed by studying the effect of TC-PTP
on PRL-induced transcriptional activation of the ß-casein gene
promoter. TC-PTP was transfected into COS-7 cells together with PRL
receptor, STAT5a or STAT5b, and the ß-casein gene promoter-luciferase
construct. A ß-galactosidase gene was also included to normalize for
transfection efficiency. Luciferase activity was determined in extracts
from cells left untreated or stimulated with PRL. As shown in Fig. 4F, transcriptional induction of ß-casein gene promoter was completely
suppressed, when TC-PTP wild type was coexpressed (lanes 4 and 12).
Consistent with suppression of endogenous ß-casein gene expression,
coexpression of catalytically inactive forms of TC-PTP suppressed
transcriptional activation of the ß-casein gene promoter (lanes 6, 8,
14, and 16).
Overexpression of TC-PTP Does Not Inhibit Nuclear Translocation of
STAT5, but Accelerates Its Export Back to Cytosol
Next, subcellular localization of STAT5 was examined in
TC-PTP-expressing COMMA-1D cells. At the indicated time points after
PRL stimulation, cells were lysed, and cytosolic and nuclear fractions
were prepared. As shown in Fig. 5, until
30 min after PRL stimulation, subcellular localization of STAT5 in
TC-PTP-expressing cells was similar to that in mock infectants, where
the amounts of cytosolic STAT5 protein gradually reduced after PRL
stimulation and, conversely, the amounts of nuclear protein increased.
However, significant amounts of STAT5 were detected in the cytosolic
fraction of TC-PTP wild type-expressing cells, and conversely nuclear
STAT5 was reduced 40 min after PRL stimulation, whereas TC-PTP mutant
exhibited no effect on the subcellular localization of STAT5 at the
same time point, suggesting that nuclear dephosphorylation of STAT5 by
TC-PTP accelerated its export back to cytosol. In PTP1B-expressing
cells, STAT5 was retained in the cytosol throughout the time points
after PRL stimulation. TC-PTP wild type as well as catalytically
inactive mutants were localized mostly (>90% as determined
densitometorically) in nucleus, whereas PTP1B mostly (>90%) in
cytosol throughout PRL stimulation. Faint bands in the nuclear
fractions for PTP1B and in the cytosolic fractions for TC-PTP were
always detected, possibly due to experimental limitation for
subcellular fractionation protocol used.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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It has been reported that IL-2-activated STAT5 is dephosphorylated by a cytoplasmic phosphatase SHP-2 in cytosol (10), although the phosphatase was shown to be involved in PRL-mediated signaling in a positive fashion (11, 12). PRL-activated STAT5 was not dephosphorylated by SHP-2 and was, instead, efficiently dephosphorylated by PTP1B in cytosol in reconstituted COS-7 cells as well as in mammary epithelial COMMA-1D cells (11, 12, 13). Although PTP1B was the first one that could dephosphorylate PRL-activated STAT5 in vivo, we could not rule out the possibility that other cytoplasmic, nuclear, or membrane-spanning PTPs were involved in PRL signaling, because most of the PTPs identified were also shown to be down-regulated in lactating mammary glands (14). Simply assumed from the suppressed gene expression of most of the PTPs in lactating mammary gland, PTP1B as well as other PTPs might cooperatively contribute to dephosphorylation of STAT5 in their respective subcellular compartments.
In the present study we showed that a nuclear phosphatase,
TC-PTP, could clearly dephosphorylate PRL-activated STAT5a and STAT5b,
but the degree of dephosphorylation activity appeared to be weaker
than that of PTP1B 30 min after PRL stimulation in transfected
COS-7 cells (Fig. 2) (13) as well as in COMMA-1D
mammary epithelial cells (Fig. 4), although both PTPs could
dephosphorylate STAT5 to the same extent in vitro (Fig. 3A).
This was reasoned by the data that tyrosine phosphorylation of STAT5 in
TC-PTP-expressing cells were scarce and indistinguishable from
those in PTP1B-expressing cells 40 min following PRL stimulation (Fig. 4, B and C), suggesting that nuclear translocation of STAT5 was
necessary for its dephosphorylation by TC-PTP, and therefore, further
time was required for its efficient dephosphorylation by the
phosphatase (Figs. 4 and 5).
Dephosphorylated STAT5 protein in nucleus should be exported back to
cytosol for subsequent recycling. In COMMA-1D cells expressing TC-PTP
wild type, most of STAT5 was retained in nucleus 30 min after PRL
stimulation, although approximately 80% of the protein was
dephosphorylated compared with mock infectants (Fig. 4, B and C).
Further incubation resulted in nearly complete dephosphorylation of
STAT5 (Fig. 4, B and C) and appearance of cytosolic STAT5 concomitant
with reduction in nuclear STAT5, but still a significant amount of
STAT5 was present in nucleus (Fig. 5). This apparent time lag might
reflect a complex mechanism for STAT5 nuclear export back through
unidentified molecules, which might also be regulated by TC-PTP.
Most of ectopically expressed PTP1B (>90%) was localized in cytosol,
whereas TC-PTP (>90%) in nucleus in mammary epithelial cells
regardless of PRL stimulation (Fig. 5). Although all the data in our
present and previous studies were obtained by overexpression study, we
suggest that such dual localization of the two different inhibitory
PTPs guarantees proper regulation of post-PRL receptor signaling by
dephosphorylating and deactivating STAT5 in vivo.
PTP1B-null mice have been available (20, 21), whereas the
use of TC-PTP null mice has been limited, because they die between 3
and 5 wk of age (22). A greater physiological relevance of
PTP1B and TC-PTP in mammary epithelial cells could be clarified using
the cells isolated from the gene-disrupted mice. However, based on our
findings that both TC-PTP and PTP1B are potent inhibitors of PRL
signaling, no phenotype might be observed when the cells have a single
gene disruption, possibly due to biological redundancy.
Localization of nuclear TC-PTP was unchanged throughout PRL stimulation
(Fig. 5), whereas it has been reported that nuclear TC-PTP, which is
the same one focused in the present study, translocated to cytosol upon
EGF stimulation and inhibited the EGF-dependent activation of PI3K and
PKB/Akt (23, 24), suggesting that localization of nuclear
TC-PTP is differentially regulated by individual ligand stimulation.
Nuclear localization of TC-PTP throughout PRL stimulation suggests that
dimerized STAT5 through its phosphotyrosine and SH2 domains is attacked
by TC-PTP possibly in a competitive manner, leading to the formation of
a stable complex between the molecules, and that TC-PTP does not
function as a chaperon for nuclear translocation of STAT5 from
cytosol.
STAT5a and STAT5b were dephosphorylated by recombinant TC-PTP and were
coimmunoprecipitated with catalytically inactive forms, so-called
substrate-trapping mutants of TC-PTP (Fig. 3), indicating that STAT5a
and STAT5b are specific substrates for not only PTP1B
(13), but also TC-PTP. Roughly estimated, 30% and 40% of
phosphorylated STAT5 were coimmunoprecipitated with Cys/Ser and Asp/Ala
mutant of TC-PTP, respectively (data not shown). On the other hand,
phosphorylated STAT5 could be precipitated only upon using excess
amounts of GST fusion proteins of PTP1B substrate-trapping mutants
(13), but not specific antibody (data not shown),
suggesting that STAT5 is a more preferred in vivo substrate
for TC-PTP. Partially inconsistent with coimmunoprecipitation data,
substrate-trapping mutants of TC-PTP suppressed endogenous ß-casein
gene expression in COMMA-1D epithelial cells (Fig. 4E) as well as
ß-casein gene promoter activation in COS-7 cells to the similar
extent as TC-PTP wild type. This might be in part explained by the fact
that coimmunoprecipitation data do not necessarily reflect the in
vivo situation, possibly due to experimental limitation and/or
that TC-PTP might also contribute to deactivation of STAT5 through to
date unidentified mechanisms.
EGF receptor and insulin receptor have also been identified to be
specific and common substrates of TC-PTP (23) and PTP1B
(25), whereas a distinct set of proteins was
coprecipitated with the PTPs (23) despite the extensive
similarity between TC-PTP and PTP1B catalytic domains (72%; Fig. 1).
It might be interesting to examine whether sequence-dependent and/or
conformational similarities among tyrosine-phosphorylated STAT5, EGF
receptor, and insulin receptor exist for dephosphorylation of the
proteins by TC-PTP and PTP1B. In addition to STAT5, it has been
reported that the PRL stimulation resulted in tyrosine phosphorylation
of STAT1 and STAT3 (26). Whether TC-PTP as well as PTP1B
are involved in negative regulation of other JAK-STAT pathways is
currently being studied in our laboratory.
The TC-PTP is an intracellular nontransmembrane phosphatase that was originally cloned from a human T cell cDNA library (27), but is now known to be expressed in many tissues. TC-PTP contains a conserved catalytic domain and a noncatalytic C-terminal segment that varies in size and function as a result of alternative splicing (28). Two splice variants differing only in their extreme C-termini are expressed. The 48-kDa form of human TC-PTP contains a 34-residue hydrophobic tail as PTP1B, which is replaced by a hydrophilic 6-residue sequence in the 45-kDa form. The 48-kDa form of TC-PTP localizes to the endoplasmic reticulum (29, 30), whereas under basal conditions the 45-kDa form is localized in the nucleus due to the presence of a bipartite nuclear localization sequence (15, 28, 30, 31, 32). In this study we examined the involvement of the 45-kDa form of mouse TC-PTP in PRL-mediated signaling, because it was actually expressed in mammary epithelial cells (14), and the cDNA sequence for the 48-kDa form has been unavailable. Although the 45-kDa form of mouse TC-PTP was shown to be active in nucleus and dephosphorylate STAT5, it remains uncertain at present whether the 48-kDa form of mouse TC-PTP locates in ER and dephosphorylates STAT5 in mammary epithelial cells.
Recently, Wang et al. (33) reported that a
small amphipathic 
-helical region was required for
proteasome-dependent turnover of the tyrosine-phosphorylated STAT5a,
and accordingly, truncation of the C-terminal region of STAT5a resulted
in prolonged tyrosine phosphorylation, suggesting that the C-terminal
small region is involved in tyrosine dephosphorylation. We examined the
dephosphorylation activity of PTP1B and TC-PTP on the truncated forms
of STAT5a and STAT5b in transfected COS-7 cells, but the degree of
dephosphorylation was indistinguishable from that of STAT5a and STAT5b
wild type. Furthermore, PTP1B and TC-PTP dephosphorylation activity was
insensitive to proteasome inhibitor MG132 (Aoki, N., et al.
unpublished observations). Therefore, we still cannot rule out the
possibility that other phosphatases might be involved in
dephosphorylation of STAT5.
In conclusion, we demonstrated nuclear dephosphorylation and deactivation of STAT5 by TC-PTP. Our previous and current studies suggest that PRL-activated STAT5 is cooperatively regulated by PTPs in both cytosol and nucleus.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mouse TC-PTP (S52655) was amplified by RT-PCR using the primer set: 5'-CTG-TCC-GCT-GTG-GTA-GTT-CC-3' (nucleotides 22–41) and 5'-GCT-GCA-GAA-TAG-TCT-CAA-GT-3' (nucleotides 1220–1239). HA-tagging to TC-PTP at its N-terminal was performed by PCR amplification using 5'-CCA-CCA-TGT-ACC-CAT-ACG-ACG-TCC-CAG-ACT-ACG-CTT-CGG-CAA-CCA-TCG-AGC-GG-3' and the above- mentioned antisense primer. All of the PCR products were cloned into a mammalian expression vector, pTargeT vector (Promega Corp., Madison, WI), and confirmed by sequencing on both strands. The HA-tagged TC-PTP mutants containing a cysteine to serine alteration at position 216 and an aspartic acid to a alanine at position 182 were generated using oligonucleotide primers 5'-CCG-CAC-TGC-TAT-GGA-TCA-3' and 5'-AAC-CCC-AAA-AGC-TGG-CCA-GGT-3', respectively, as previously described (34). The mutation was confirmed by DNA sequencing.
Expression plasmids for mouse PRL receptor (pCMX-PL1), mouse STAT5a (pXM-mSTAT5a), and STAT5b (pXM-mSTAT5b) were provided by Dr. B. Groner (Institute for Experimental Cancer Research, Freiburg, Germany).
Cell Culture, Transfection, Cell Lysis, Subcellular
Fractionation, and Western Blotting
COS-7 and COMMA-1D cells were maintained in DMEM containing 10%
FCS and transfected as previously described (35). After
stimulation with PRL (5 µg/ml) for the indicated time, cells were
lysed, followed by immunoprecipitation and Western blotting with the
respective antibodies or by biochemical cell fractionation as
previously described (13).
Retrovirus-Mediated Gene Delivery
HA-tagged TC-PTP was ligated into pLXSN retroviral vector
(CLONTECH Laboratories, Inc., Palo Alto, CA) via
EcoRI site and introduced into Pheonix ecotropic packaging
cells. COMMA-1D cells were infected with the retrovirus-containing
culture medium and then selected in the presence of G418 (1 mg/ml) for
2 wk. To eliminate clonal deviation, G418-resistant polyclonal cells
were used for subsequent experiments.
In Vitro Dephosphorylation Assay
GST fusion proteins containing full-length TC-PTP were
constructed as follows. Full-length TC-PTP was PCR amplified using a
primer set of 5'-ATGAATTCTCGGCAACCATGGAGCGG-3' and
5'-GCT-GCA-GAA-TAG-TCT-CAA-GT-3' with pTargeT-HA-TC-PTPs as templates,
and the resultant products were digested with EcoRI and
ligated into pGEX-5X-1 vector (Amersham Pharmacia Biotech)
through the same cloning site. GST fusion proteins were purified on
glutathione-Sepharose beads and eluted with neutralized glutathione.
Enzymatic activities of the GST fusion proteins were determined using
para-nitrophenyl phosphate, as described previously (36).
STAT5a and STAT5b immune complexes prepared from PRL-treated COS-7
cells that had been cotransfected with PRL receptor and STAT5a were
processed and incubated with indicated GST fusion proteins as
previously described (13).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication June 14, 2001. Accepted for publication September 14, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-helical region
is required for transcriptional activities and proteasome-dependent
turnover of the tyrosine-phosphorylated Stat5. EMBO J 19:392–399[CrossRef][Medline]
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
).
