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NEOPLASIA
From the DNAX Research Institute of Molecular and
Cellular Biology, Palo Alto, CA, and the Division of Pediatric Oncology
and Cellular and Molecular Biology, Dana Farber Cancer Institute,
Harvard Medical School, Boston, MA.
Cytokines, such as interleukin-2 (IL-2), activate intracellular
signaling pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell
growth and survival. The deubiquitinating enzyme DUB-2 is induced in
response to IL-2 but as yet its function has not been determined. The
results of this study show that DUB-2 is expressed in human T-cell
lymphotropic virus-I(HTLV-1)-transformed T cells that exhibit
constitutive activation of the IL-2 JAK/STAT (signal transducers and
activators of transcription) pathway, and when expressed in Ba/F3 cells
DUB-2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although
DUB-2 did not enhance IL-2-mediated proliferation, when withdrawn from
growth factor, cells expressing DUB-2 had sustained STAT5
phosphorylation and enhanced expression of IL-2-induced genes
cis and c-myc. Moreover,
DUB-2 expression markedly inhibited apoptosis induced by cytokine
withdrawal allowing cells to survive. Taken together these data suggest
that DUB-2 can enhance signaling through the JAK/STAT pathway, prolong
lymphocyte survival, and, when constitutively expressed, may contribute
to the activation of the JAK/STAT pathway observed in some transformed cells.
(Blood. 2001;98:1935-1941) The survival, proliferation, and differentiation of
lymphocytes are controlled by cytokines that act through specific
transmembrane receptors.1 Interleukin-2 (IL-2) regulates
T-cell survival through a receptor composed of 3 chains, IL-2R Although the activation of the receptor signaling pathways has been
studied in detail, how these processes are regulated is unclear. One
important mechanism of signal transduction regulation is the
dephosphorylation of signaling intermediates by protein tyrosine
phosphatases such as SHP-1 and phospholipid phosphatases like
SHIP.4 Recent studies have identified 2 new families of negative regulatory molecules termed suppressors of cytokine signaling (SOCS/JAB/SSIs) and protein inhibitors of activated STATs (PIAS), which
suppress signal transduction via the JAK-STAT pathway possibly by
directly inhibiting JAK kinases and receptor-mediated STAT activation.5,6
Additionally, proteolytic degradation is also a suggested mechanism for
the regulation of receptor turnover, and a number of receptors can be
targeted for endocytosis and proteolytic degradation by
ubiquitination.7 Recently, the ubiquitin (Ub)-mediated
proteolytic pathway has been implicated in many intracellular processes
such as transcriptional activation, cell cycle regulation, and the turnover of plasma membrane receptors such as the c-Kit receptor. Proteins that are targeted for degradation are conjugated with a
76-amino acid Ub polypeptide tag. This is accomplished via a series of
enzymes termed the Ub-conjugating complex consisting of components
including Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3)
enzymes.8 Polyubiquitinated proteins are then targeted to
the proteasome where degradation can occur. Deubiquitinating enzymes
are a family of cysteine proteases that cleave Ub from Ub-conjugated
protein substrates and hence also control ubiquitination.9 Deubiquitinating enzymes can act at many points in the Ub pathway including polyubiquitin chain processing, removing Ub from substrates to rescue from degradation, or by removing residual Ub to assist in
proteasomal degradation. Many novel candidate deubiquitinating enzymes
have been identified indicating that these enzymes may be the largest
group involved in the Ub system.10 These deubiquitinating enzymes or Ub-processing proteases (UBPs) have considerable sequence diversity and are therefore likely to have a broad range of
specificities. However, their substrate specificities and function have
not been determined.
Recently 2 cytokine-inducible genes have been described that belong to
a novel class of deubiquitinating enzymes termed DUB-1 and
DUB-2.10 They were identified as hematopoietic-specific immediate-to-early genes that are rapidly induced after cytokine stimulation. DUB-1 is induced by IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and is expressed in a variety of
hematopoietic cells types, but DUB-2 appears to be specifically regulated by IL-2 and its expression is restricted to T
cells.11-13 The function of these enzymes is not known,
but the fact that both DUB-1 and DUB-2 are induced after cytokine
stimulation suggests that they may play a role in cytokine-mediated
signal transduction.
To determine DUB-2 function we expressed the enzyme in a Ba/F3
B-lymphocyte cell line and found that it enhanced IL-2 receptor and
STAT5 tyrosine phosphorylation in response to IL-2. We also detected
DUB-2 expression in human T-cell lymphotropic virus I (HTLV-1)-transformed T cells that exhibit constitutive activation of
the IL-2 JAK/STAT pathway. When DUB-2 was expressed in
IL-2R Plasmids
Cell culture and transfections
Apoptosis assays The Ba/F3 /tTA DUB-2 cells were grown out of tetracycline for
48 hours, rested for 12 hours, stimulated with IL-2 for 4 to 5 hours,
and then withdrawn from IL-2 for the indicated period. Apoptotic cells
were quantified by standard trypan blue exclusion assay using a 0.4%
trypan blue stain solution (Gibco BRL), or by flow cytometry after
propidium iodine (PI) staining as follows. Cells were washed once in
phosphate-buffered saline (PBS), resuspended in a hypotonic buffer
containing 0.1% nonylphenoxy polyethoxy ethanol (NP-40), 0.1% sodium
citrate, and 50 µg/mL PI (Sigma, St Louis, MO), and subjected
to flow cytometry analysis using FACSCalibur and CellQuest
software (Becton Dickinson, Franklin Lakes, CA).
Immunoprecipitations and Western blotting Cells were washed in PBS, lysed in 10 mM Tris pH 7.5, 150 mM NaCl, 2 mM EDTA, 0.875% Brij 96, 0.125% NP-40, 1 mM Na3VO4, 5 mM NaF, 10 µg/mL leupeptin, 10 µg/mL aprotinin, and 1 mM p-nitrophenyl p'-guanidine benzoate (NPGB), and centrifuged at 18 000g at 4°C for 15 minutes. Lysates were immunoprecipitated using either monoclonal antibody (mAb) IL-2R,24 polyclonal DUB,12
antibodies to STAT5b, monoclonal M2 anti-FLAG (Sigma), or mAb
to ERK2 (Santa Cruz Biotechnology). The immunoprecipitates were washed
5 times in lysis buffer, and separated on sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred
onto polyvinylidene difluoride (PVDF) membranes (Millipore,
Bedford, MA), and immunoblotted. Antibodies used were as
follows: FLAG epitope (Octapeptide epitope, Zymed), DUB,12 DUB-2 (rabbit polyclonal no. 305), Bcl-x
(Transduction Laboratories, San Diego, CA), phosphotyrosine mAb
(4G10, UBI), phospho-Akt and Akt (New England Biolabs, Beverly,
MA), STAT5b, IL-2R, c-Myc, phospho-ERK and ERK-2 mAb (Santa
Cruz Biotechnology), and Cis (a gift from Dr A. Yoshimura). The blots
were visualized by enhanced chemoluminescence (ECL; Pierce,
Rockford, IL).
DUB-2 is constitutively expressed in HTLV-1-transformed MT2 cells Considerable evidence suggests that the JAK/STAT pathway plays a positive role in leukemia.14 Indeed oncogenic transformation of T cells by HTLV-1 can result in constitutive tyrosine phosphorylation of the IL-2 receptor complex and STAT5.15-17 To explore IL-2-induced genes that were expressed in HTLV-1-transformed T cells, we examined DUB-2 expression in MT-2 cells using an antibody that recognizes DUB-1 and DUB-2.12 We compared DUB protein expression in MT2 cells, Ba/F3 cells (pro-B cell), and MOLT-4 cells (T-cell leukemia) before and after 4 hours of IL-2 stimulation (Figure
1A). Although no induction of DUB protein
was detected in Ba/F3 cells, a protein of 64 to 68 kd was recognized by
the DUB-specific antibody in MOLT-4 cells after IL-2
treatment. The apparent molecular weight of the protein (64 kd) and the
fact that it was seen in an IL-2-responsive T-cell line such as
MOLT-4 suggested that it was human DUB-2. Interestingly,
MT-2 showed a protein of the same size that was constitutively
expressed prior to IL-2 treatment and further induced by IL-2. Although
the IL-2 signaling pathway was constitutively active in MT2 cells,
expression of other IL-2-induced genes including SOCS3 and
CIS was not observed (results not shown). Therefore in an
HTLV-1-transformed T-cell line DUB-2 is uniquely stably expressed,
perhaps suggesting that it may play a role in transformation.
Proteasome inhibitors block dephosphorylation of the IL-2 receptor and STAT5 Deubiquitinating enzymes such as DUB-2 can block Ub- and proteasome-mediated proteolytic degradation.10 Two recent reports have suggested that signaling via the EPO receptor18 and the IL-3 receptor19 can be regulated in a proteasome-dependent manner. To explore whether the Ub system was involved in the regulation of IL-2 signaling we tested the effect of the proteasome inhibitor MG132. KIT-225 cells were preincubated in media containing MG132 (5 µM) or control dimethyl sulfoxide (DMSO) for 1 hour, and then treated with IL-2 for 20 minutes prior to washing and resuspension in media without IL-2. Cell lysates were immunoprecipitated with an antibody to the IL-2R, run on
SDS-PAGE, and blotted for antiphosphotyrosine. IL-2-induced rapid
tyrosine phosphorylation of the IL-2R chain was evident at 20 minutes, and following withdrawal from IL-2 the level of IL-2R
phosphorylation returned to background within 1 hour in cells not
treated with proteasome inhibitor (Figure 1B, upper panel). However, in
the presence of MG132 the level of IL-2R tyrosine phosphorylation
had not decreased by 1 hour but remained elevated up to 2 hours
following cytokine withdrawal (Figure 1B, upper panel). Interestingly
the JAK kinases JAK1 and JAK3 also coprecipitated with the IL-2R and in
the presence of MG132 remained associated and phosphorylated up to 1 hour following IL-2 removal. Reblotting with anti-IL-2R antibody
showed equivalent protein in each lane. This finding suggested that
turnover of the phosphorylated IL-2R complex required
proteasome-mediated degradation. To determine whether proteasome
inhibitors affected other components of the IL-2 signaling pathway, we
examined the phosphorylation of the STAT5b using the same lysates. In
DMSO-treated cells IL-2-induced STAT5 tyrosine phosphorylation was not
detected 2 hours after cytokine withdrawal, but remained elevated up to 2 hours in the presence of MG132 (Figure 1B, lower panels). This effect
on IL-2-induced STAT5 has been reported previously and coupled with
our data suggest that proteasome inhibitors can stabilize both IL-2R
and STAT5 phosphorylation, suggesting that their dephosphorylation was
dependent on the proteasome pathway and perhaps the Ub system.
STAT5 phosphorylation is prolonged in cells expressing DUB-2 Having found that IL-2R and STAT5 dephosphorylation can be inhibited by a proteasome-dependent mechanism, and that DUB-2 was constitutively expressed in adult T-cell leukemia (ATL) cells, we wondered whether IL-2-induced phosphorylation might be affected by DUB-2. Because neither DUB-2 nor DUB-1 was detected in Ba/F3 cells following IL-2 treatment (Figure 1A), we made Ba/F3 cells that stably expressed DUB-2 (and IL-2R) and explored IL-2-induced STAT5 and
IL-2R phosphorylation. The cells were treated with IL-2 for the
periods shown and the lysates immunoprecipitated with anti-IL-2R,
run on SDS-PAGE, and blotted with antiphosphotyrosine. IL-2-induced
phosphorylation of the IL-2R was not significantly altered in cells
expressing DUB-2 (Figure 2A, upper
panel). We then examined IL-2-mediated STAT5 phosphorylation, by
immunoprecipitating with anti-STAT5b and blotting for phosphotyrosine.
In control BA/F3 cells IL-2-induced tyrosine phosphorylation of
STAT5b returned to almost basal levels by 2 hours (Figure 2A, lower
panels). However, in cells expressing DUB-2, STAT5b phosphorylation was
markedly prolonged with phosphorylation still detected at 2 hours.
These findings suggest that when DUB-2 is expressed it can prolong
IL-2-mediated STAT5 phosphorylation.
As previously reported, DUB-2 is induced in response to IL-2 and is not
expressed in resting lymphocytes. Thus it is possible that sustained
expression of DUB-2 may affect many proteasome-dependent events. We
therefore created Ba/F3 cells containing tTA such that DUB-2 expression
was induced on removal from tetracycline, and examined tyrosine
phosphorylated STAT5 following IL-2 treatment. Cells grown for 48 hours
either in the presence or absence of tetracycline were stimulated with
IL-2 for up to 12 hours, and tyrosine phosphorylated STAT5 examined. In
cells not expressing DUB-2 (Figure 2B, +Tet) IL-2-induced tyrosine
phosphorylation of STAT5 returned to background levels by 3 hours.
However, in cells expressing DUB-2 (Figure 2B, DUB-2 inhibits STAT5 dephosphorylation Dephosphorylation of signaling intermediates occurs rapidly after removal of cytokine. We therefore wanted to determine whether STAT5 phosphorylation would remain elevated after cytokine withdrawal in cells expressing DUB-2. Cells were stimulated with IL-2 for 2 hours, washed, and incubated in cytokine-free medium for the indicated times and tyrosine- phosphorylated STAT5 was examined both in cells removed from or maintained in tetracycline. In cells not expressing DUB-2 IL-2-induced tyrosine phosphorylation of STAT5b was not detected 20 minutes following cytokine withdrawal (Figure 3, +Tet, top panel). However, in cells expressing DUB-2, STAT5b phosphorylation was still observed at 1 hour after cytokine removal (Figure 3, Tet, top panel). To examine whether
DUB-2 could prolong phosphorylation of other signaling intermediates we
checked IL-2-mediated ERK-2 and AKT phosphorylation. ERK-2 phosphorylation was observed up to1 hour after cytokine withdrawal whether or not DUB-2 was expressed (Figure 3, third panel). The level
of ERK-2 expression in both cells was comparable (Figure 3, fourth
panel). No significant difference in AKT phosphorylation was observed
between cells expressing and not expressing DUB-2 (Figure 3, fifth
panel). Thus, DUB-2 expression can markedly inhibit dephosphorylation
of STAT5, but not ERK-2 or AKT, following cytokine withdrawal,
suggesting that DUB-2 may specifically enhance JAK/STAT signaling.
DUB-2 enhances the expression of STAT5-induced gene products We next wished to examine whether the prolonged activation of STAT5 would result in extended expression of the IL-2-induced STAT5-dependent genes such as the cytokine-induced SH2-containing protein (CIS). CIS can be strongly induced by many cytokines that activate STAT5, including IL-2, and its expression had been reported to be dependent on STAT5.20 CIS expression was examined in the lysates described above by immunoblotting with an antibody specific for CIS (Figure 3, eighth panel). In the presence of DUB-2 CIS expression was markedly prolonged up to 8 hours following cytokine withdrawal, whereas it was not detected beyond 2 hours in the absence of DUB-2. We also observed markedly enhanced expression of c-Myc, a gene also known to be activated by STAT5 (Figure 3, ninth panel).21 However, Bcl-x protein levels were not affected in cells expressing DUB-2 (Figure 3, tenth panel). Bcl-x was shown to be STAT5 regulated,22 but in these cells Bcl-x protein was expressed in unstimulated cells and its expression was not further enhanced by IL-2 stimulation. Taken together these findings suggest that DUB-2 expression can prolong the expression of STAT5-regulated genes in lymphocytes.DUB-2 inhibits apoptosis following cytokine withdrawal Although DUB-2 could prolong IL-2-mediated signaling, its expression in Ba/F3 cells did not enhance cytokine-mediated proliferation (results not shown). We therefore wondered whether DUB-2 might improve the survival of cells withdrawn from growth factor. Tetracycline-responsive cells were stimulated with IL-2 for 4 hours, withdrawn from cytokine, and survival-monitored using standard assays. In Figure 4A, cell death was monitored by trypan blue exclusion at different periods following removal from cytokine. Two days after cytokine withdrawal 100% loss of cell viability was evident in cells not expressing DUB-2. By contrast, at 2 days 35% of cells that expressed DUB-2 were resistant to cell death induced by cytokine withdrawal. Even 5 days after cytokine withdrawal 10% of the cells expressing DUB-2 still did not take up trypan blue (Figure 4A). This effect was evident in over 10 experiments in 3 separate DUB-2 clones and the data suggest that DUB-2 can strongly inhibit apoptosis induced by cytokine withdrawal.
Apoptosis was also monitored by PI staining and flow cytometry analysis
(Figure 4B). Apoptotic cells correspond to the cell population
localized in the sub-G1 peak (M1). Twenty-eight
hours after IL-2 withdrawal 95% of Ba/F3
In the present study, we show that the deubiquitinating enzyme
DUB-2 can enhance IL-2-mediated signaling and can serve to suppress
apoptosis in lymphocytes following withdrawal of growth factor. We
found that DUB-2 was constitutively expressed in HTLV-1-transformed T
cells that exhibit STAT5 activation and growth factor independence. Cells that expressed DUB-2 had prolonged phosphorylation of STAT5 and
enhanced expression of STAT5-dependent genes. It would be interesting
to examine whether serine phosphorylation of STAT5 and tyrosine
phosphorylation of STAT3 are affected by DUB-2 expression. Unfortunately, we did not detect STAT3 tyrosine phosphorylation in
response to IL-2 in Ba/F3 cells expressing IL-2R We clearly found that DUB-2 could prolong STAT5 phosphorylation induced by IL-2 and maintained STAT5 activation on cytokine withdrawal. However, we did not observe STAT5 constitutive activation in DUB-2-expressing cells without prior cytokine stimulation. This suggests that although the activation of STAT5 was prolonged in the presence of DUB-2, it required cytokine-induced receptor activation. In these experiments, no clear effect of DUB-2 on IL-2R phosphorylation was detected, suggesting that the receptor may not be a direct target for DUB-2. We have also observed enhanced IL-3-mediated STAT5 phosphorylation in cells expressing DUB-2, but only at times earlier than 2 hours following IL-3 treatment (data not shown). This IL-3 result is complicated by DUB-1, the DUB-2 homologue, which is known to be expressed in Ba/F3 cells 2 hours after IL-3 treatment.12 Because DUB-1 and DUB-2 are close homologues, this result is difficult to interpret, but perhaps both deubiquitinating enzymes can enhance STAT5 activation and therefore the expression of STAT5-dependent genes and hence improve survival in more physiologic concentrations of cytokine. How DUB-2 enhances IL-2-mediated phosphorylation is unknown, but our
data suggest that regulation of the JAK/STAT pathway likely involves
the Ub system and several mechanisms could be proposed. First, DUB-2
may inhibit dephosphorylation by blocking the activity of a phosphatase
and this would be supported by the observation that proteasome
inhibitors prolong STAT5 phosphorylation (Callus and
Mathey-Prevot,19 Verdier et al,20 and this
study), and also by the observation that STAT5 phosphorylation is
maintained on IL-2 withdrawal (Figure 3). Second, STAT phosphorylation
is clearly controlled by phosphatases such as SHP-123 and
other proteins such as SOCS3 and CIS,24-26 and it is
possible that deubiquitinating enzymes regulate these STAT-inhibitory
molecules. However, CIS expression is up-regulated in cells expressing
DUB-2 (Figure 3), making it unlikely that DUB-2 prolongs Stat5
phosphorylation through this family of STAT inhibitors. Third, DUB-2
may inhibit STAT turnover. However, this seems unlikely because
ubiquitination of STAT5 has not been detected, and because Wang and
colleagues27 reported that proteasome inhibitors have no
effect on STAT5 half-life. Fourth, receptor turnover may be affected by
DUB-2. Interestingly, the Whether the antiapoptotic effect observed with DUB-2 can be mimicked by other DUB family members is unclear. Zhu and coworkers11 reported that DUB-1 can force cells into the G1 phase of the cell cycle and hence has proposed that DUB-1 may function to inhibit cell proliferation. We have also found that DUB-2 can inhibit cell proliferation and, following IL-2 withdrawal, cells that express DUB-2 survive longer and accumulate in G1. Because DUB-1 is induced by IL-3 and GM-CSF and is expressed in a variety of hematopoietic cell types, it may be important for survival of other cell types such as hematopoietic stem cells and the myeloid lineage. It should be pointed out that a strong survival effect was also observed in DUB-2-expressing cells on IL-3 withdrawal (data not shown), which may be the result of not only DUB-2 but also DUB-1 expression. Our data support the idea that DUBs do not enhance proliferation, but rescue from programmed cell death, and may therefore be important in directing cell survival in vivo. Many forms of leukocyte transformation are associated with activation of the JAK/STAT pathway and STAT5, in particular, contributes to transformation mediated by v-ABL29 and BCR/ABL.30,31 BCR/ABL-dependent STAT5 activation has been shown to be important for protection from apoptosis and for growth factor independence. Indeed an oncogenic mutation of STAT5A is known to induce growth factor independence in Ba/F3 cells. In our hands DUB-2 can prolong STAT5 phosphorylation but was not sufficient to induce proliferation because these cells did not multiply independent of growth factor, but we have found that some cells that express DUB-2 can become growth factor-independent (results not shown). Human T-cell lymphotropic virus I is the etiologic agent for ATL
and tropical spastic paraparesis (TSP/HAM [HTLV-1-associated myelopathy]).32-33 HTLV-1-transformed T-cell
lines that proliferate independently of IL-2 have constitutively
activated IL-2 signaling.16 The transcriptional
transactivator Tax, encoded by HTLV-1, can enhance expression of genes
such as IL2R Deubiquitinating enzymes some such as FAF (fat facets in
Drosophila) can cleave Ub from specific targets regulating cellular pools of free Ub. Other enzymes remove Ub from cellular proteins and
rescue from Ub-mediated degradation, whereas yet others accelerate proteasome-mediated degradation by removing Ub from degradation remnants.10,11 It will be important to explore whether
deubiquitinating enzymes such as Fam, which can interact with and
stabilize the oncogene In conclusion, the observation that DUB-2 is expressed in ATL cells and may prolong cell survival suggests that it may be important for transformation. Key remaining questions include the mechanisms responsible for the prolonged phosphorylation of STAT5 and the mechanism by which DUB-2 may inhibit cell death. Nonetheless, this is the first report that a deubiquitinating enzyme can enhance survival, and although the mechanism will require further investigation, the findings clearly show an important role for the Ub pathway in the regulation of cell survival.
We thank Dr Bruno Amati for critical comments and Maribel Andonian for graphics.
Submitted March 13, 2001; accepted May 17, 2001.
The DNAX Research Institute is fully supported by Schering-Plough.
T.-S.M., M.H., and A.R. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: James A. Johnston, Department of Immunology, Whitla Medical Building, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7BL, Northern Ireland; e-mail: jim.johnston{at}qub.ac.uk.
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  J. F. Burrows, A. A. Kelvin, C. McFarlane, R. E. Burden, M. J. McGrattan, M. De la Vega, U. Govender, D. J. Quinn, K. Dib, M. Gadina, et al. USP17 Regulates Ras Activation and Cell Proliferation by Blocking RCE1 Activity J. Biol. Chem., April 3, 2009; 284(14): 9587 - 9595. [Abstract] [Full Text] [PDF]
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K.-H. Baek, M.-S. Kim, Y.-S. Kim, J.-M. Shin, and H.-K. Choi DUB-1A, a Novel Deubiquitinating Enzyme Subfamily Member, Is Polyubiquitinated and Cytokine-inducible in B-lymphocytes J. Biol. Chem., January 23, 2004; 279(4): 2368 - 2376. [Abstract] [Full Text] [PDF]
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E. S. Tien, J. P. Gray, J. M. Peters, and J. P. Vanden Heuvel Comprehensive Gene Expression Analysis of Peroxisome Proliferator-treated Immortalized Hepatocytes: Identification of Peroxisome Proliferator-activated Receptor {alpha}-dependent Growth Regulatory Genes Cancer Res., September 15, 2003; 63(18): 5767 - 5780. [Abstract] [Full Text] [PDF]
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E. M. Hanson, H. Dickensheets, C.-K. Qu, R. P. Donnelly, and A. D. Keegan Regulation of the Dephosphorylation of Stat6. PARTICIPATION OF TYR-713 IN THE INTERLEUKIN-4 RECEPTOR alpha , THE TYROSINE PHOSPHATASE SHP-1, AND THE PROTEASOME J. Biol. Chem., January 31, 2003; 278(6): 3903 - 3911. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
,
IL-2R
c). Binding of IL-2 to its
receptor results in activation of the cytoplasmic tyrosine kinases JAK1
and JAK3, which, in turn, induce phosphorylation of the receptor and
associated signaling molecules including the signal transducers and
activators of transcription (STATs).
