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Hagedorn Research Institute (J.A.H., K.L., J.H.N., N.B.)
DK-2820 Gentofte, Denmark
The Walter and Eliza Hall Institute
for Medical Research (D.J.H.) Parkville, Victoria 3052,
Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The induction of SOCS gene expression by cytokines has been
reported in a number of different cell types both in vitro
and in vivo. Stimulation of CIS and SOCS-1, -2, and -3 mRNA
expression in bone marrow cells by Epo, thrombopoietin,
granulocyte-colony stimulating factor (G-CSF), leukemia-inhibiting
factor (LIF), granulocyte macrophage-colony stimulating factor
(GM-CSF), IL-1, -2, -3, -4, -6, -7, -12, -13, and interferon-
(IFN-) has been reported (2). In this study great variation in
inducibility was observed with some cytokines inducing the expression
of all four SOCS mRNA (GM-CSF and IFN) while others induced only a
subset of the SOCS genes. In BaF3 cells, IL-2 and IL-3 induced the
expression of CIS (4, 7), and in M1 cells both IL-6 and LIF induced the
induction of SOCS-1 and CIS while no induction of SOCS-2 and -3 was
observed. In 3T3-F442A preadipocytes, GH induced a rapid and transient
expression of SOCS-3 and, to a lesser extent, SOCS-1 (8). In the
hypothalamus, leptin has been reported to induce the expression of
SOCS-3 mRNA, and increased levels of SOCS-3 mRNA were observed in the
hypothalamus of the obese lethal yellow (Ay/a) mouse, which
is known to exhibit leptin resistance (9).
SOCS-1 was originally identified by its ability to inhibit IL-6-induced M1 cell differentiation (2) and by its binding to the kinase domain of JAK2 (5), indicating an inhibitory action in IL-6 signaling at the level of the JAK2 kinase. Subsequently it was demonstrated that SOCS-1 inhibited the intrinsic kinase activity of all four JAK family members when overexpressed in COS or 293 cells (5). In accordance with this observation, it was reported that SOCS-1 inhibited IL-6-induced tyrosine phosphorylation of STAT3, the IL-6 receptor-signaling subunit gp130 and JAK2 (10). In contrast, it was found that SOCS-3 and CIS were unable to inhibit the intrinsic kinase activity of JAK2, and it was proposed that these SOCS proteins inhibit cytokine signaling at a step distal to JAK activation. CIS has been shown to interact directly with the phosphorylated Epo and GM-CSF receptors, and it was suggested that this binding might prevent the recruitment of STAT factors to the receptor/JAK complex.
The SOCS proteins can be divided into three domains: the N terminus exhibiting little sequence identity among the SOCS proteins, the centrally located SH2 domain, and the SOCS box located in the C terminus (2). Recently it has been found that both the N terminus and SH2 domain of SOCS-1 were required for suppression of IL-6 and LIF signaling and inhibition of JAK activity (11). The SH2 domain and an additional N-terminal 12 amino acids of SOCS-1 were found to be required for interaction with tyrosine 1007 in the activation loop of JAK2 and thus inhibition of kinase activity (12). The SOCS box of SOCS-1 is not required for its inhibitory activity but rather seems to be involved in protein stability (13), possibly by interacting with elongins B and C (14).
GH preferentially induces the expression of SOCS-3 (8), and since it has been observed that SOCS-3, in contrast to SOCS-1, could not inhibit the intrinsic kinase activity of JAK2, we have in this study investigated the mechanism by which SOCS-1 and SOCS-3 inhibit signaling by the GH receptor. We have identified specific domains of SOCS-1 and SOCS-3 involved in the suppression of GH-mediated transcription, STAT5 activation, and JAK2 activity, and binding to the tyrosine-phosphorylated GH receptor.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). Coexpression of either
SOCS-1 or SOCS-3 inhibited GH-induced transcription in a dose-dependent
manner, while coexpression of CIS did not affect GH induction.
Expression of SOCS-2 resulted in a slightly higher induction by GH as
compared with control.
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, B and C. The construction of chimeric
SOCS proteins was facilitated by the introduction of specific
restriction sites between the N-terminal domain and the SH2 domain and
between the SH2 domain and the SOCS box. The activity of the SOCS
proteins containing these introduced restriction sites was found to be
identical to that of the wild-type SOCS proteins (Fig. 2A
vs. Fig. 1
). Analyzing the chimeric SOCS proteins revealed
that the SOCS box was interchangeable and did not confer specificity,
since SOCS proteins having the SOCS box of CIS and the N-terminal and
SH2 domains of SOCS-1 or SOCS-3 were able to inhibit GH-induced
transcription (Fig. 2B). In contrast, the N-terminal domain was able to
confer specificity as shown by the inhibitory effect of chimeric SOCS
proteins having the N-terminal domain of SOCS-1 or SOCS-3 and the SH2
domain and the SOCS box from CIS (Fig. 2C).
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. The linker domain in SOCS-1 consists
of only 5 amino acids while that of SOCS-3 has 47 amino acids (Fig. 3C). The activity of SOCS-1 was not altered by removing the SOCS box
and 3 amino acids of the linker domain, leaving only 2 amino acids
C-terminal to the SH2 domain, whereas in SOCS-3 46 amino acids of the
linker domain were required for function. Thus, in both SOCS proteins,
the SOCS box was dispensable, but SOCS-3 requires amino acids located
between positions 177 and 184.
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). In cells transfected with SOCS-1 or
SOCS-3, no STAT5 DNA binding could be detected. Western blot analysis
using total cell extracts revealed that STAT5 was expressed at
comparable levels in all cell extracts (Fig. 4B). The level of SOCS
protein expression was highest in cells transfected with CIS and lowest
in SOCS-3-transfected cells (Fig. 4C).
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and 6).
It was demonstrated that the same chimeric SOCS proteins that could
inhibit GH-induced transcription also inhibited STAT5 activity.
Furthermore, we found that the region of the linker domain in SOCS-3
required for inhibition of transcription was also required for
inhibition of STAT5 activity.
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). By
immunoprecipitation of JAK2 followed by Western blot analysis using
antiphosphotyrosine antibodies, we observed that only SOCS-1 and not
SOCS-2, SOCS-3, or CIS was able to inhibit tyrosine phosphorylation of
the kinase (Fig. 7).
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). The amount of SOCS protein applied in
each reaction was evaluated by including a sample of cell lysate from
nontransfected cells and from each of the cell lysates used for the
binding reactions (lanes 7–9 and 16–18).
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). None of the nonphosphorylated
peptides affected SOCS-3 binding to the GST-GH receptor fusion
protein.
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). From this
experiment it was observed that none of the SOCS proteins could inhibit
STAT5 binding to the receptor, even though an approximately 50-to
250-fold molar excess of SOCS protein compared with STAT5 was used.
This finding suggests that SOCS-3 does not inhibit STAT5 binding to the
GH receptor and that the inhibition of STAT5 by SOCS-3 cannot be
explained by competition for binding sites within the GH receptor.
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). These
observations indicate that SOCS-3 binding to the GH receptor plays an
important role in the mechanism by which it suppresses GH-mediated
signaling.
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), a reduced amount of JAK2-encoding plasmid was used in this
experiment, resulting in a GH-inducible and GH receptor-dependent
tyrosine phosphorylation of JAK2. By immunoprecipitation of JAK2
followed by Western blot analysis using antiphosphotyrosine antibodies,
we observed that SOCS-3 was able to inhibit GH-induced tyrosine
phosphorylation of JAK2 (Fig. 12).
Inhibition of this tyrosine phosphorylation of the kinase was observed
using 3 µg GH receptor expression plasmid, and further inhibition of
the GH-induced tyrosine phosphorylation of JAK2 was observed using
10 µg GH receptor expression plasmid. This finding suggests that
SOCS-3 can inhibit JAK2 tyrosine phosphorylation by a mechanism
dependent on the GH receptor.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The C-terminal 40-amino acid region of the SOCS proteins has been
termed the SOCS box, and this domain exhibits approximately 50%
identity among the SOCS family members. The functional role of this
domain is not known as it has been reported to be not required for
inhibition of IL-6-induced transcription or JAK kinase activation. In
this study we found that the SOCS box is not important for inhibition
of GH-induced transcription by SOCS-1 and SOCS-3. However, the linker
region between the SH2 domain and the SOCS box of SOCS-3 was required
for SOCS-3 to inhibit GH signaling. This linker region is considerably
longer in SOCS-3 compared with SOCS-1 (Fig. 3). Inhibitory activity was
observed when only two amino acids of the linker region were present in
SOCS-1, whereas almost the entire linker region (46 amino acids) was
required for SOCS-3 inhibition of GH-induced transcription. The same 46
amino acids were also required for inhibition of GH-induced activation
of STAT5.
Previous studies have shown that CIS is able to bind to the tyrosine-phosphorylated erythropoietin and IL-3 receptors (4), and it was suggested that CIS binding to these receptors reduces the interaction between STAT5 and the receptor, resulting in inhibition of STAT5 activation. Using GST-GH receptor fusion proteins, we could show that all four SOCS proteins were able to bind specifically to the tyrosine-phosphorylated GH receptor. It was also demonstrated that binding of SOCS-3 to the GST-GH receptor fusion protein was inhibited by a phosphopeptide containing tyrosine 487, whereas phosphopeptides containing either tyrosine 534, 595, or 627 were less inhibitory and phosphopeptide 566 inhibited only slightly. Since we previously identified three of these tyrosine residues (Y534, Y566, and Y627) as STAT5 binding sites (15, 16) in the GH receptor, we tested whether SOCS-3 could compete with STAT5 for binding to the GH receptor. However, no competition could be observed, suggesting that the inhibitory mechanism of SOCS-3 in GH signaling was not by competing for STAT5 binding sites in the GH receptor. The fact that Y566 did not bind SOCS-3 but is able to bind STAT5 might explain the lack of competition between these two factors. The observation that all four SOCS members are able to bind to the GH receptor also suggests that binding to the receptor is not sufficient for inhibition of GH signaling. The role of SOCS binding to the GH receptor is not known at present; however, we found that the same region of the linker domain in SOCS-3 that was required for inhibition of GH-induced signaling was also required for binding to the GH receptor. This finding was surprising since the SH2 domain is believed to be able to bind phosphotyrosines by itself, but in the case of SOCS-3 an additional 46 amino acids C-terminal to the SH2 domain seem to be required for this binding.
Thus, these data in combination with the observations that only SOCS-1 was able to inhibit tyrosine phosphorylation of overexpressed JAK2, whereas SOCS-3 was able to inhibit GH-stimulated tyrosine phosphorylation of JAK2 only in the presence of the GH receptor, indicate that SOCS-1 and SOCS-3 inhibit GH signaling by two different mechanisms. It is tempting to suggest that SOCS-1 directly binds to the JAK2 kinase and thereby inhibits the kinase activity, whereas SOCS-3 only inhibits JAK2 kinase activity after binding to the GH receptor. This hypothesis furthermore predicts that two functional domains are present in the SOCS proteins: one, which includes the SH2 domain, is involved in binding of the SOCS protein to phosphotyrosines in cytokine receptors or in JAK kinases, and the other, which includes the N-terminal domain, is involved in the actual inhibition of kinase activity. Interestingly, a similar difference in the mechanism by which GH activates STAT1 and STAT5 was previously reported (17). STAT1 is activated by a mechanism that does not require GH receptor tyrosine phosphorylation (18), whereas STAT5 activation by GH is dependent upon phosphorylation of at least one of three tyrosines in the intracellular domain of the GH receptor (16, 19).
The physiological role of SOCS proteins in GH signaling is not known at present; however, since SOCS-3 is the major SOCS protein induced by GH both in vitro and in vivo, this factor is presumed to be the main regulator of GH signaling. The transient nature of SOCS-3 mRNA induction by GH and the relative short half-life of SOCS-3 protein suggests that SOCS-3 acts in a classical negative feed-back loop, suppressing GH signaling for a limited time period. Interestingly GH is secreted in a pulsatile manner in most species with a frequency of 3 to 4 h between each peak. This time period is in good agreement with the time required for SOCS-3 levels to return to basal levels after a GH pulse, and the role of SOCS-3 might be to protect against overstimulation by GH or alternatively to restrict the time in which a cell is responsive to GH stimulation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Cell Culture
Chinese hamster ovary (CHO) cells were cultured in Ham’s
F-12 medium (Life Technologies, Inc., Gaithersburg, MD)
supplemented with 10% FCS, 100 U/ml penicillin, and 100 µg/ml
streptomycin. Cells were transfected at 90% confluency in 60-mm cell
culture dishes. Twenty-four hours before transfection, cells were
washed twice and incubated with 3 ml serum free GC3 medium (1:1 mixture
of DMEM and Ham’s F-12 (Life Technologies, Inc.),
adjusted to pH 7.1 with 7.5% NaHCO3 solution, supplemented
with 10 µg/ml transferrin, 160 mU/ml insulin, 2 mM
L-glutamine, 2 mM nonessential amino acids, 100
U/ml penicillin, and 100 µg/ml streptomycin). Cells were transiently
transfected by calcium phosphate precipitation as described previously
(15). Each dish was transfected with 0.01–1 µg SOCS expression
vector, 3 µg pCH110 ß-galactosidase expression vector, 1.5 µg Spi
2.1/chloramphenicol acetyltransferase (CAT) plasmid, and 1.5 µg GH
receptor expression plasmid, and cultured in the absence or presence of
20 nM hGH (Novo Nordisk, Bagsvaerd,
Denmark) overnight. CAT assay was performed on total cellular
extracts as described (22) using ß-galactosidase as an internal
control. Human kidney 293 cells were cultured in DMEM supplemented with
10% heat-inactivated FCS, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 2 mM L-glutamine. Cells were
seeded in 100-mm cell culture dishes with 10 ml culture medium and
transiently transfected the next day (50% confluency) by calcium
phosphate precipitation.
Peptides
Synthetic peptides were purchased from Affinity Research
Products Ltd. (Mamhead, UK) either nonphosphorylated or tyrosine
phosphorylated. Five 13 amino acid long peptides derived from the GH
receptor were synthesized; LANIDFYAQVSDI (peptide Y487), FIMDNAYFCEADA
(peptide Y534), FNQEDIYITTESL (peptide Y566), EMPVPDYTSIHIV (peptide
Y595), and FLSSCGYVSTDQL (peptide Y627). The peptides were purified by
HPLC and their composition verified by mass spectrometry.
GST-GHR Binding Assay
Cell extracts were isolated by addition of lysis buffer (50
mM HEPES, pH 7.2, 250 mM NaCl, 10% glycerol, 2
mM EDTA, 2 mM EGTA, 0.1% NP-40, 1
mM 4-(2-aminoethyl) benzene sulfonyl fluoride
(AEBSF), 1 µg/ml aprotinin, 1 µg/ml leupeptin, 10 µg/ml
herbimycin, and 1 mM sodium orthovanadate) to the cells
followed by 20 min incubation on ice. After centrifugation at
10,000 x g for 10 min at 4 C, the supernatants were
used for GST binding assays. Varying amounts (indicated in each
individual experiment) of the extracts were added to 50 µl (50%)
glutathione-Sepharose 4B beads to which 25 µg of GST fusion protein
were bound and incubated for 12–14 h at 4 C with rotation (when
competition with GH receptor peptides was performed, the peptide was
added before the cell lysate). The Sepharose pellets were then washed
five times with ice-cold lysis buffer and analyzed by Western blot
analysis.
GST Fusion Proteins
The cDNA encoding the membrane-proximal region or the
carboxy-terminal region of the rat GH receptor was amplified by PCR
from the GH receptor plasmid pLM 108. PCR products were ligated into
the GST fusion vector pGEX-5X-3 (Pharmacia Biotech,
Piscataway, NJ). The resulting plasmids were sequenced to verify the
fidelity of PCR and to confirm proper, in-frame cloning. Induction and
affinity purification of GST proteins and GST-GH receptor fusion
proteins were performed as recommended by the manufacturer
(Pharmacia Biotech). In addition, GST proteins and
tyrosine-phosphorylated GST-GH receptor fusion proteins were
induced and purified from the Escherichia coli TKX1 strain
that harbors a plasmid-encoded inducible tyrosine kinase gene as
recommended by the manufacturer (Stratagene, La Jolla,
CA).
Immunoprecipitation
Protein G-Sepharose (Pharmacia Biotech) and 1–10
µl of the respective antibody were added to the cell lysate (prepared
in IP buffer: 50 mM Tris/HCl, pH 7.5, 0.1 M
Triton X-100, 137 mM NaCl, 2 mM EGTA, 1
mM AEBSF, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 1
mM sodium orthovanadate), and samples were incubated 12–14
h at 4 C. Samples were washed three times with IP buffer, and the
pellets were then washed five times with ice-cold lysis buffer and
analyzed by SDS-PAGE and Western blot analysis.
Nuclear Extracts and Electrophoretic Mobility Shift Assay
(EMSA)
Cells were cultured with or without GH (20 nM) for 5
min, washed twice with ice-cold PBS, and lysed in buffer A (20
mM HEPES, pH 7.9, 10 mM KCl, 1 mM
MgCl2, 1 mM EDTA, 1 mM
dithiothreitol, 0.5 mM AEBSF, 1 mM sodium
orthovanadate, 1 µg/ml aprotinin, 1 µg/ml leupeptin, and 20%
glycerol) containing 0.5% Triton X-100. After 5 min of incubation on
ice, the nuclei were collected by centrifugation at 2500 x
g for 7 min at 4 C. The nuclei were resuspended in 5 volumes
of a hypertonic buffer (buffer A containing 400 mM NaCl)
and incubated on a rocking platform for 30 min at 4 C. The supernatant
was collected after centrifugation at 20,000 x g for
30 min at 4 C. The double-stranded Spi 2.1 GLE1 oligonucleotide
(5'-agctATGTTCTGAGAAAATC-3' and 5'-agctGATTTTCTCAGAACAT-3') was
32P-labeled in a fill-in reaction using
[
-32P]dCTP and DNA polymerase (Klenow fragment).
Approximately 20 fmol probe were used per reaction with 10 µg nuclear
extract in EMSA buffer (100 mM HEPES, pH 7.9, 10
mM NaCl, 1 mM MgCl2, 1
mM EDTA, 10% glycerol) containing 0.1 µg/µl
double-stranded poly dI/dC (polydeoxyinosinic-deoxycytidylic acid).
EMSA reactions were preincubated for 30 min at 30 C before separation
on a 5% polyacrylamide gel containing 2% glycerol and 0.25% TBE (25
mM Tris/HCl, 25 mM boric acid, and 0.25
mM EDTA, pH 7.9). The gel was dried and exposed to x-ray
film.
Construction of SOCS Mutants
SOCS chimera expression vectors were generated by introduction
of ClaI sites (between the N-terminal domain and the SH2
domain) and NotI sites (between the SH2 domain and the
SOCS-box) in the various SOCS-encoding plasmids using the Quickchange
site-directed mutagenesis kit (Stratagene). The plasmids
were digested with XbaI/ClaI, and cDNA fragments
encoding the following amino acid sequences were purified: CIS (1–79
and 80–257); SOCS-1 (1–77 and 78–212); and SOCS-3 (1–43 and
44–225). The plasmids were also digested with
XbaI/NotI, and cDNA fragments encoding the
following amino acid sequences were purified: CIS (1–210 and
211–257); SOCS-1 (1–174 and 175–212); and SOCS-3 (1–184 and
185–225). The various SOCS domain swap mutants were generated by
cross-ligation of appropriate fragments, e.g.
(fragments 1, 3, and 3) encoding SOCS-1 (1–77) fused to SOCS-3
(44–225), etc. The different SOCS mutants encoding truncated forms of
SOCS-1 and SOCS-3 were generated by introducing stop codons using the
Quickchange site-directed mutagenesis kit
(Stratagene).
Western Blot Analysis
Proteins were resolved by SDS-PAGE (4% stacking gel, 7.5%,
10%, or 12% running gel) and transferred by electroblotting to
ECL nitrocellulose membranes (Amersham Pharmacia Biotech,
Arlington Heights, IL). Membranes were blocked for 1 h in TBST
buffer (50 mM Tris/HCl, pH 7.4, 150 mM NaCl,
and 0.1% Tween 20) containing 5% nonfat dry milk. Primary antibody
diluted in TBST was added, and the blot was incubated for 1 h at
room temperature. After three successive 20-min washes with TBST, the
secondary antibody was added and membranes were incubated for 1
additional hour, and the proteins were visualized by the ECL detection
system according to the manufacturer’s instructions (Amersham Pharmacia Biotech).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Johnny A. Hansen and Karen Lindberg are supported by the Danish Research Academy. Part of this work was supported by The National Health and Medical Research Council, Canberra, Australia, The NIH, Bethesda, Maryland (Grant CA-22556), and the Australian Federal Government’s Cooperative Research Centre Program.
Received for publication April 29, 1999. Revision received July 16, 1999. Accepted for publication July 20, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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 F. Giordanetto and R. T. Kroemer A three-dimensional model of Suppressor Of Cytokine Signalling 1 (SOCS-1) Protein Eng. Des. Sel., February 1, 2003; 16(2): 115 - 124. [Abstract] [Full Text] [PDF]
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C. J. Greenhalgh, D. Metcalf, A. L. Thaus, J. E. Corbin, R. Uren, P. O. Morgan, L. J. Fabri, J.-G. Zhang, H. M. Martin, T. A. Willson, et al. Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling J. Biol. Chem., October 18, 2002; 277(43): 40181 - 40184. [Abstract] [Full Text] [PDF]
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 S.-E. Kong, S. M. Firth, R. C. Baxter, and P. J. D. Delhanty Regulation of the acid-labile subunit in sustained endotoxemia Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E692 - E701. [Abstract] [Full Text] [PDF]
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O. Morales, M. H. Faulds, U. J. Lindgren, and L.-A. Haldosen 1alpha ,25-Dihydroxyvitamin D3 Inhibits GH-induced Expression of SOCS-3 and CIS and Prolongs Growth Hormone Signaling via the Janus Kinase (JAK2)/Signal Transducers and Activators of Transcription (STAT5) System in Osteoblast-like Cells J. Biol. Chem., September 13, 2002; 277(38): 34879 - 34884. [Abstract] [Full Text] [PDF]
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S. G. Ronn, J. A. Hansen, K. Lindberg, A. E. Karlsen, and N. Billestrup The Effect of Suppressor of Cytokine Signaling 3 on GH Signaling in {beta}-Cells Mol. Endocrinol., September 1, 2002; 16(9): 2124 - 2134. [Abstract] [Full Text] [PDF]
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G. Yumet, M. L. Shumate, P. Bryant, C.-M. Lin, C. H. Lang, and R. N. Cooney Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E472 - E481. [Abstract] [Full Text] [PDF]
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S. Ji, S. J. Frank, and J. L. Messina Growth Hormone-induced Differential Desensitization of STAT5, ERK, and Akt Phosphorylation J. Biol. Chem., August 9, 2002; 277(32): 28384 - 28393. [Abstract] [Full Text] [PDF]
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 G. K. Geiss, M. Salvatore, T. M. Tumpey, V. S. Carter, X. Wang, C. F. Basler, J. K. Taubenberger, R. E. Bumgarner, P. Palese, M. G. Katze, et al. Cellular transcriptional profiling in influenza A virus-infected lung epithelial cells: The role of the nonstructural NS1 protein in the evasion of the host innate defense and its potential contribution to pandemic influenza PNAS, August 6, 2002; 99(16): 10736 - 10741. [Abstract] [Full Text] [PDF]
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 D. L. Krebs, R. T. Uren, D. Metcalf, S. Rakar, J.-G. Zhang, R. Starr, D. P. De Souza, K. Hanzinikolas, J. Eyles, L. M. Connolly, et al. SOCS-6 Binds to Insulin Receptor Substrate 4, and Mice Lacking the SOCS-6 Gene Exhibit Mild Growth Retardation Mol. Cell. Biol., July 1, 2002; 22(13): 4567 - 4578. [Abstract] [Full Text] [PDF]
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C. M. Silva, M. T. Kloth, A. J. Whatmore, J. S. Freeth, N. Anderson, K. K. Laughlin, T. Huynh, A. J. Woodall, and P. E. Clayton GH and Epidermal Growth Factor Signaling in Normal and Laron Syndrome Fibroblasts Endocrinology, July 1, 2002; 143(7): 2610 - 2617. [Abstract] [Full Text] [PDF]
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C. J. Greenhalgh, P. Bertolino, S. L. Asa, D. Metcalf, J. E. Corbin, T. E. Adams, H. W. Davey, N. A. Nicola, D. J. Hilton, and W. S. Alexander Growth Enhancement in Suppressor of Cytokine Signaling 2 (SOCS-2)-Deficient Mice Is Dependent on Signal Transducer and Activator of Transcription 5b (STAT5b) Mol. Endocrinol., June 1, 2002; 16(6): 1394 - 1406. [Abstract] [Full Text] [PDF]
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V. Beauloye, B. Willems, V. de Coninck, S. J. Frank, M. Edery, and J.-P. Thissen Impairment of Liver GH Receptor Signaling by Fasting Endocrinology, March 1, 2002; 143(3): 792 - 800. [Abstract] [Full Text] [PDF]
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L. Gonzalez, J. G. Miquet, A. I. Sotelo, A. Bartke, and D. Turyn Cytokine-Inducible SH2 Protein Up-Regulation Is Associated with Desensitization of GH Signaling in GHRH-Transgenic Mice Endocrinology, February 1, 2002; 143(2): 386 - 394. [Abstract] [Full Text] [PDF]
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S.-H. Park, H. Yamashita, H. Rui, and D. J. Waxman Serine Phosphorylation of GH-Activated Signal Transducer and Activator of Transcription 5a (STAT5a) and STAT5b: Impact on STAT5 Transcriptional Activity Mol. Endocrinol., December 1, 2001; 15(12): 2157 - 2171. [Abstract] [Full Text] [PDF]
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F. Dif, E. Saunier, B. Demeneix, P. A. Kelly, and M. Edery Cytokine-Inducible SH2-Containing Protein Suppresses PRL Signaling by Binding the PRL Receptor Endocrinology, December 1, 2001; 142(12): 5286 - 5293. [Abstract] [Full Text] [PDF]
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S.-H. Park and D. J. Waxman Inhibitory Cross-talk between STAT5b and Liver Nuclear Factor HNF3beta . IMPACT ON THE REGULATION OF GROWTH HORMONE PULSE-STIMULATED, MALE-SPECIFIC LIVER CYTOCHROME P-450 GENE EXPRESSION J. Biol. Chem., November 9, 2001; 276(46): 43031 - 43039. [Abstract] [Full Text] [PDF]
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G. S. Tannenbaum, H. K. Choi, W. Gurd, and D. J. Waxman Temporal Relationship Between the Sexually Dimorphic Spontaneous GH Secretory Profiles and Hepatic STAT5 Activity Endocrinology, November 1, 2001; 142(11): 4599 - 4606. [Abstract] [Full Text] [PDF]
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S. P. Tam, P. Lau, J. Djiane, D. J. Hilton, and M. J. Waters Tissue-Specific Induction of SOCS Gene Expression by PRL Endocrinology, November 1, 2001; 142(11): 5015 - 5026. [Abstract] [Full Text] [PDF]
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A. E. Karlsen, S. G. Ronn, K. Lindberg, J. Johannesen, E. D. Galsgaard, F. Pociot, J. H. Nielsen, T. Mandrup-Poulsen, J. Nerup, and N. Billestrup Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-1beta - and interferon-gamma -mediated toxicity PNAS, September 26, 2001; (2001) 211445998. [Abstract] [Full Text] [PDF]
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C. J. Greenhalgh and D. J. Hilton Negative regulation of cytokine signaling J. Leukoc. Biol., September 1, 2001; 70(3): 348 - 356. [Abstract] [Full Text] [PDF]
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A. Flores-Morales, L. Fernandez, E. Rico-Bautista, A. Umana, C. Negrin, J.-G. Zhang, and G. Norstedt Endoplasmic Reticulum Stress Prolongs GH-Induced Janus Kinase (JAK2)/Signal Transducer and Activator of Transcription (STAT5) Signaling Pathway Mol. Endocrinol., September 1, 2001; 15(9): 1471 - 1483. [Abstract] [Full Text] [PDF]
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A. W. Roberts, L. Robb, S. Rakar, L. Hartley, L. Cluse, N. A. Nicola, D. Metcalf, D. J. Hilton, and W. S. Alexander Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3 PNAS, July 31, 2001; 98(16): 9324 - 9329. [Abstract] [Full Text] [PDF]
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B. N. Friedrichsen, E. D. Galsgaard, J. H. Nielsen, and A. Møldrup Growth Hormone- and Prolactin-Induced Proliferation of Insulinoma Cells, INS-1, Depends on Activation of STAT5 (Signal Transducer and Activator of Transcription 5) Mol. Endocrinol., January 1, 2001; 15(1): 136 - 148. [Abstract] [Full Text]
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A. Colson, A. Le Cam, D. Maiter, M. Edery, and J.-P. Thissen Potentiation of Growth Hormone-Induced Liver Suppressors of Cytokine Signaling Messenger Ribonucleic Acid by Cytokines Endocrinology, October 1, 2000; 141(10): 3687 - 3695. [Abstract] [Full Text] [PDF]
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E. LeBel, L. Vallieres, and S. Rivest Selective Involvement of Interleukin-6 in the Transcriptional Activation of the Suppressor of Cytokine Signaling-3 in the Brain during Systemic Immune Challenges Endocrinology, October 1, 2000; 141(10): 3749 - 3763. [Abstract] [Full Text] [PDF]
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M. R. Stofega, J. Herrington, N. Billestrup, and C. Carter-Su Mutation of the SHP-2 Binding Site in Growth Hormone (GH) Receptor Prolongs GH-Promoted Tyrosyl Phosphorylation of GH Receptor, JAK2, and STAT5B Mol. Endocrinol., September 1, 2000; 14(9): 1338 - 1350. [Abstract] [Full Text]
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 D. DUVAL, B. REINHARDT, C. KEDINGER, and H. BOEUF Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF) -dependent embryonic stem cell survival FASEB J, August 1, 2000; 14(11): 1577 - 1584. [Abstract] [Full Text]
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B. Emanuelli, P. Peraldi, C. Filloux, D. Sawka-Verhelle, D. Hilton, and E. Van Obberghen SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling J. Biol. Chem., May 19, 2000; 275(21): 15985 - 15991. [Abstract] [Full Text] [PDF]
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 D. Krebs and D. Hilton SOCS: physiological suppressors of cytokine signaling J. Cell Sci., January 8, 2000; 113(16): 2813 - 2819. [Abstract] [PDF]
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A. Sasaki, H. Yasukawa, T. Shouda, T. Kitamura, I. Dikic, and A. Yoshimura CIS3/SOCS-3 Suppresses Erythropoietin (EPO) Signaling by Binding the EPO Receptor and JAK2 J. Biol. Chem., September 15, 2000; 275(38): 29338 - 29347. [Abstract] [Full Text] [PDF]
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P. A. Ram and D. J. Waxman Role of the Cytokine-inducible SH2 Protein CIS in Desensitization of STAT5b Signaling by Continuous Growth Hormone J. Biol. Chem., December 8, 2000; 275(50): 39487 - 39496. [Abstract] [Full Text] [PDF]
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T. J. Pircher, J. N. Geiger, D. Zhang, C. P. Miller, P. Gaines, and D. M. Wojchowski Integrative Signaling by Minimal Erythropoietin Receptor Forms and c-Kit J. Biol. Chem., March 16, 2001; 276(12): 8995 - 9002. [Abstract] [Full Text] [PDF]
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C. Bjorbak, H. J. Lavery, S. H. Bates, R. K. Olson, S. M. Davis, J. S. Flier, and M. G. Myers Jr. SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985 J. Biol. Chem., December 15, 2000; 275(51): 40649 - 40657. [Abstract] [Full Text] [PDF]
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R. A. Mooney, J. Senn, S. Cameron, N. Inamdar, L. M. Boivin, Y. Shang, and R. W. Furlanetto Suppressors of Cytokine Signaling-1 and -6 Associate with and Inhibit the Insulin Receptor. A POTENTIAL MECHANISM FOR CYTOKINE-MEDIATED INSULIN RESISTANCE J. Biol. Chem., July 6, 2001; 276(28): 25889 - 25893. [Abstract] [Full Text] [PDF]
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D. Metcalf, S. Mifsud, L. Di Rago, N. A. Nicola, D. J. Hilton, and W. S. Alexander Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1) PNAS, January 22, 2002; 99(2): 943 - 948. [Abstract] [Full Text] [PDF]
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S. E. Nicholson, D. De Souza, L. J. Fabri, J. Corbin, T. A. Willson, J.-G. Zhang, A. Silva, M. Asimakis, A. Farley, A. D. Nash, et al. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130 PNAS, June 6, 2000; 97(12): 6493 - 6498. [Abstract] [Full Text] [PDF]
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A. E. Karlsen, S. G. Ronn, K. Lindberg, J. Johannesen, E. D. Galsgaard, F. Pociot, J. H. Nielsen, T. Mandrup-Poulsen, J. Nerup, and N. Billestrup Suppressor of cytokine signaling 3 (SOCS-3) protects beta -cells against interleukin-1beta - and interferon-gamma -mediated toxicity PNAS, October 9, 2001; 98(21): 12191 - 12196. [Abstract] [Full Text] [PDF]
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