HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 277, Issue 43, 40181-40184, October 25, 2002

This Article Abstract Full Text (PDF) All Versions of this Article: 277/43/40181    most recent C200450200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Greenhalgh, C. J. Articles by Hilton, D. J. Search for Related Content PubMed PubMed Citation Articles by Greenhalgh, C. J. Articles by Hilton, D. J.

ACCELERATED PUBLICATION
Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling^*

Christopher J. Greenhalgh^§, Donald Metcalf, Anne L. Thaus, Jason E. Corbin, Rachel Uren, Phillip O. Morgan, Louis J. Fabri^¶, Jian-Guo Zhang, Helene M. Martin, Tracy A. Willson, Nils Billestrup, Nicos A. Nicola, Manuel Baca, Warren S. Alexander, and Douglas J. Hilton

From  The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research for Cellular Growth Factors, PO Royal Melbourne Hospital, VIC 3050, Australia, ^¶ AMRAD Operations Ltd., Richmond 3121, Australia, and the  Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark

Received for publication, August 9, 2002

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation of cytokine signaling. The generation of SOCS-2-deficient mice, which grow to one and a half times the size of their wild-type littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate signaling. To determine whether a similar enhancement of signaling is observed in vivo or alternatively whether increased SOCS-2 levels repress growth in vivo, we generated and analyzed transgenic mice that overexpress SOCS-2 from a human ubiquitin C promoter. These mice are not growth-deficient and are, in fact, significantly larger than wild-type mice. The overexpressed SOCS-2 was found to bind to endogenous GH receptors in a number of mouse organs, while phosphopeptide binding studies with recombinant SOCS-2 defined phosphorylated tyrosine 595 on the GH receptor as the site of interaction. Together, the data implicate SOCS-2 as having dual effects on GH signaling in vivo.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The suppressor of cytokine signaling (SOCS)¹ proteins are a family of eight SH2 domain-containing proteins, comprising cytokine-inducible SH2 domain-containing protein (CIS) and SOCS-1-7. Studies in many laboratories have implicated SOCS proteins in the attenuation of cytokine action through inhibition of the Janus kinase (JAK)/signal transducer and activators of transcription (STAT) signal transduction pathway. SOCS proteins operate as part of a classical negative feedback loop, in which activation of cytokine signaling leads to their expression. Once produced, SOCS proteins bind to key components of the signaling apparatus to prevent further signal transduction and possibly target them for degradation via a conserved C-terminal motif, called the SOCS Box, that recruits ubiquitin ligases (reviewed in Refs. 1-3).

While in vitro studies have suggested that SOCS proteins may be promiscuous in their activity, gene deletion studies in mice have highlighted their importance in a limited number of signaling pathways. SOCS-1 is a key regulator of interferon  signaling, T-cell homeostasis, and lactation (4-6), while SOCS-3 is thought to play a crucial role in placental function (7). CIS-deficient mice are reported to have no phenotype, although CIS transgenic mice display growth retardation and defects in mammary development which are accompanied by reductions in STAT5 phosphorylation (8). Interestingly, this phenotype has similarities to those observed in STAT5a- and STAT5b-deficient mice (9-11).

SOCS-2-deficient animals exhibit accelerated post-natal growth resulting in a 30-50% increase in body weight by 12 weeks of age, significant increases in bone and body lengths, thickening of the skin due to collagen deposition, and increases in internal organ size (12). This phenotype has striking similarities to those of insulin-like growth factor (IGF)-I and growth hormone (GH) transgenic mice (13, 14), as well as the high growth mutant mouse (15). Further investigation of the SOCS-2^/ phenotype identified significant increases of IGF-I mRNA in some tissues and lower levels of major urinary protein, the expression of which is regulated by pulsatile GH secretion (12). Recently, STAT5 phosphorylation in response to GH has been shown to be modestly prolonged in SOCS-2^/ primary hepatocytes compared with to those from wild type mice, and much of the acceleration of growth in SOCS-2^/ mice requires the presence of STAT5b, a key mediator of GH action (16).

The biochemical mechanism by which SOCS-2 suppresses GH action remains largely unknown. SOCS-2 mRNA expression is induced by GH (17, 18), but overexpression studies in vitro to define the effects of SOCS-2 on GH action have been ambiguous. Some reports show SOCS-2 to moderately inhibit GH signaling (19, 20), others suggest SOCS-2 may enhance signaling (18, 21), while others have shown SOCS-2 to suppress signaling at low doses and enhance signaling at higher doses (22). Here we report on the generation of mice that transgenically overexpress SOCS-2 and find that these mice display no apparent growth retardation as might be predicted, but rather are larger than wild-type littermates in a number of growth parameters. With these mice we demonstrate that SOCS-2 interacts with endogenous GH receptors in primary cells, and using synthesized peptides we have mapped an important site of SOCS-2 interaction to Tyr⁵⁹⁵ of the GH receptor.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Generation of Transgenic Mice-- SOCS-2 transgenic mice were generated by ligating the mouse SOCS-2 coding region into the pUbiFLAG vector in which expression of the gene of interest is driven by the human ubiquitin C promoter (23). Transgenic mice were generated as previously described in Ref. 23. Mice carrying the SOCS-2 transgene were bred to establish whether they transmitted them to progeny, then Northern blotting was performed as described previously (24) on RNA from a range of tissues to evaluate expression.

Growth Analysis-- Growth curves, organ weights, and bone measurements were performed as described previously (12).

Analysis of Protein Expression/Interaction in SOCS-2 Transgenic Mice-- Protein extracts and immunoprecipitation experiments from tissues were prepared and performed essentially as described (23), except that tissues were lysed in muscle lysis buffer (0.5% (v/v) Nonidet P-40, 50 mM Tris, pH 8.0, 1 mM EDTA, 150 mM NaCl, 10% (v/v) glycerol, 1 mM sodium orthovanadate, 0.5 mM phenylmethylsulfonyl fluoride, 1 mM sodium fluoride, and protease inhibitors (Roche Molecular Biochemicals)), and 40 µg of total protein from each organ lysate was blotted on Western blots and probed to determine HSP70 levels using the antibody sc-24 (Santa Cruz). Antibodies against mouse GH receptor were kindly provided by F. Talamates, University of California.

Transient Transfections-- Transfections were performed in 293T cells plated at 2 × 10⁵ cells/ml in 2 ml of DME with 10% fetal calf serum using FuGENE transfection reagents (Roche Molecular Biochemicals). Briefly, 100 ng each of GH receptor plasmid, LHRE-luc reporter plasmid (kindly provided by Dr. Jane Visvader, Walter and Eliza Hall Institute of Medical Research), -galactosidase plasmid, and 0-100 ng of pEFSOCS-2FLAG plasmid (25) made up to 100 ng with pEFBOS plasmid were transfected into a six-well plate 24 h after cells were plated out. Twenty-four hours later, cells were washed once with mouse tonicity phosphate-buffered saline (MT-PBS), and the culture medium was replaced with DME containing 1% bovine serum albumin. Cells were left to equilibrate for 1 h before 500 ng/ml of recombinant human (rh)GH was added to appropriate groups. Cells were incubated for a further 16 h before being lysed and assayed for luciferase and -galactosidase activity as described (25).

Histopathological Examination-- The heart, lungs, brain, skin, muscle, spleen, thymus, mesenteric lymph node, liver, kidneys, bladder, seminal vesicles, uterus, and testicles were collected from 12-week-old animals; weighed; and then fixed in 10% saline-buffered formalin before being sectioned, stained with hematoxylin/eosin, and analyzed as described previously (12).

Generation of Recombinant SOCS-2 Proteins-- DNA encoding the murine SOCS-2 SH-2 domain (amino acids 37-159) was amplified from the pEF-SOCS-2 plasmid by PCR and ligated into the pET-43.1 NusA fusion protein expression plasmid (Novagen). DNA encoding a hexa-His sequence was engineered into the 3' primer to aid in purification. The vector was transformed into BL21(DE3) cells, and cultures were grown at 30 °C until OD₆₀₀ was 0.6 units before being induced with 0.1 mM isopropyl--D-thiogalactopyranoside. Cells were harvested 2 h post-induction, and cell pellets were lysed in 10 ml of lysis buffer per 50 ml of culture (MT-PBS containing 0.2 mg/ml lysozyme, 1% Triton X-100, 1 mM phenylmethylsulfonyl fluoride, and 30 µg/ml DNase I) for 60 min at 4 °C. The total cell lysate was centrifuged for 10 min at 27,000 × g at 4 °C. The supernatant was then loaded onto a nickel-nitrilotriacetic acid column (Qiagen) equilibrated in buffer (50 mM sodium phosphate, 300 mM NaCl, pH 8.0), washed with buffer containing 10 mM -mercaptoethanol and 10 mM imidazole eluted with 200 mM imidazole. Fractions were collected and then EDTA and -mercaptoethanol were added to achieve final concentrations of 2 and 40 mM. Fractions that contained His-tagged proteins were pooled and applied to a size-exclusion chromatography column (Sephadex 200). Samples were subsequently analyzed by SDS-PAGE and Western blotting using anti-His antibodies (penta-His, Qiagen).

Peptide Synthesis-- Synthetic peptides with a C-terminal amide were synthesized using Fmoc (N-(9-fluorenyl)methoxycarbonyl) amino acids activated with O-benzotriazol-1-yl-N',N',N',N'-tetramethyluronium hexaflurophosphate. Peptides were biotinylated by coupling d-biotin to the N terminus of resin-bound peptides before cleavage and deprotection. Peptide products were purified by reverse phase-high performance liquid chromatography and analyzed by matrix-assisted laser desorption ionization mass spectrometry.

Recombinant SOCS-2 Protein/GH Receptor Peptide Interaction-- Biotinylated phosphopeptides were immobilized on streptavadin-agarose resin (Pierce, Brisbane, Australia) using standard procedures, and 20 µl of resin was incubated with 25 µg of NusA-SOCS-2-SH2 in 1 ml of Tris, pH 7.5, 0.1% Tween 20 for 2 h at 4 °C. Beads were then washed twice with cold PBS, 0.1% (v/v) Tween 20 and boiled in 25 µl of 2× reducing loading buffer (125 mM Tris-HCl, pH 6.8, 20% (v/v) glycerol, 4% SDS, and 5% (v/v) -mercaptoethanol). SDS-PAGE was performed on samples as described in Ref. 16.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

SOCS-2 Can Enhance and Suppress GH Signaling-- The effects of SOCS expression on GH-induced transcription were analyzed by transient transfections of 293T cells with a GH-responsive STAT5-dependent luciferase reporter, porcine GH receptor, and a -galactosidase-containing plasmid in the presence or absence of plasmids encoding CIS, SOCS-1, SOCS-2, or SOCS-3. In the absence of exogenous SOCS proteins, GH stimulation resulted in a 16-fold increase of reporter activity. The expression of increasing levels of transfected SOCS-2 initially caused repression of reporter activity to 40% of that seen in the absence of SOCS, but at higher concentrations of SOCS-2 a recovery from inhibition and a significant enhancement of reporter activity were observed (Fig. 1). Expression of SOCS-1 and SOCS-3 prevented any significant reporter activity, and CIS was also a potent inhibitor of GH-induced activity.

View larger version (35K): [in this window] [in a new window]   Fig. 1.   SOCS-2 can act as a dual effector on GH signaling. 293T cells were transfected with pig GH receptor and CIS, SOCS-1, SOCS-3, or a range of SOCS-2 concentrations (ng) were stimulated with rhGH, and the luciferase activity from a LHRE-luciferase reporter was measured. Data were corrected for transfection efficiency by co-transfection of a -galactosidase expressing plasmid and luciferase activity in the absence of GH then expressed as a percentage of wild-type (WT) activity, which is assigned a value of 100%. A sample of lysate from each group was Western blotted and probed with antibodies against FLAG. Data shown are the mean taken from three independent experiments.

Transgenic Expression of SOCS-2 Does Not Inhibit Growth, but Enhances It-- To determine whether high levels of SOCS-2 could also potentiate GH signaling in vivo, we generated SOCS-2 transgenic mice. Three independent lines of mice that transmitted the SOCS-2 transgene were produced and two of these (line F33 and line F9) were analyzed further. Expression of SOCS-2 from the transgene in these lines was confirmed by immunoprecipitation of SOCS-2 protein via the FLAG epitope from lysates of all organs examined (Fig. 2A).

View larger version (22K): [in this window] [in a new window]   Fig. 2.   Generation and analysis of SOCS-2 transgenic mice. A, expression of SOCS-2 protein was examined in a range of tissues from the F9 and F33 transgenic lines by immunoprecipitation of FLAG-tagged proteins, Western transfer, and then probing with antibodies to detect FLAG-tagged proteins. Forty µg of protein from organ lysates were blotted for Hsp70 to confirm loadings. Asterisks denote nonspecific bands. Note: FLAG-SOCS-2 is detectable in F33 line muscle samples but has not reproduced well in this figure. B, growth curves for male wild-type and transgenic mice were constructed using data from 15-36 mice at each point. A and B indicate significant differences (p < 0.05) between wild-type () and F9 (closed circles) or F33 transgenic mice (), respectively. C, differences in organ weights of 12-week-old male F9 (open bars) and F33 (closed bars) transgenic mice compared with wild-type mice are represented as a percentage increase over the mean of wild-type mouse organ weight. mes LN, sem ves, sal gland, and nose-anus refer to mesenteric lymph node, seminal vesicle, salivary gland, and nose-anus body length, respectively. Asterisks denote significant differences from wild-type mice (p < 0.05).

Given the accelerated growth in mice deficient for SOCS-2, it was interesting to observe that SOCS-2 transgenic mice suffered from no apparent growth retardation throughout the post-natal period but, rather, displayed enhanced growth. Male mice were significantly heavier from 3 weeks of age resulting in a 13-15% increase in body weight (Fig. 2B). This trend was confirmed in male organ weights with both lines, demonstrating an overall increase in the size of most organs and tissues, with some being significant enlarged, particularly the carcass (Fig. 2C). Significant changes were also found in the growth rates and body and organ weights of female transgenic mice, although they were of a lesser magnitude (data not shown).

Histological and Hematopoietic Analysis-- Histological examination of 3-month-old mice from both transgenic lines compared with wild-type mice revealed no consistent abnormalities or defects in any organ or tissue examined. No differences were detectable in white blood cells, hematocrit, or platelet numbers between groups, and normal numbers of progenitor cell-derived colonies were generated in cultures of marrow cells from transgenic mice when stimulated with a range of cytokines (data not shown). Despite data suggesting that the onset of blast crisis in patients with chronic myeloid leukemia is accompanied by the development of high levels of SOCS-2 mRNA (26), we found no indication that elevated SOCS-2 levels led either to leukemia development or to maturation arrest in hematopoeitic cells of any lineage.

SOCS-2 Interacts with the GH Receptor in Vivo-- Based on the hypothesis that SOCS-2 may regulate or bind to the GH receptor, immunoprecipitations of the SOCS-2 protein were performed from a number of tissues from wild-type and transgenic mice, before and after GH injection. These lysates were then electrophoresed and examined by Western blotting. As expected FLAG-tagged SOCS-2 was detected in transgenic but not wild-type mice, and this was observed to interact with the growth hormone receptor, especially after growth hormone injection (Fig. 3). A similar experiment was also performed where an animal was injected with IGF-I, and the Western blot was probed with antibodies against the IGF-I receptor, but no interaction was detected (data not shown).

View larger version (35K): [in this window] [in a new window]   Fig. 3.   SOCS-2 interacts with endogenous GH receptors. Organ lysates were made from C57Bl/6, SOCS-2 F33 transgenic mice, and SOCS-2 F33 transgenic mice injected with 100 µg of recombinant porcine GH 40 min previously. Anti-FLAG immunoprecipitations and Western blots were performed, then probed with antibodies against mouse GH receptor, followed by antibodies to detect FLAG.

SOCS-2 Interacts with Tyrosine 595 of the Human GH Receptor-- Previous studies have shown that SOCS-2 can interact with the phosphorylated GH receptor in vitro (19, 21), and we have shown here an in vivo association. To further define the nature of this interaction, we designed biotinylated phophotyrosine (Tyr(P)) peptides to each of the seven tyrosine residues phosphorylated on the human GH receptor in response to GH (Fig. 4A). These peptides were bound to streptavidin-Sepharose before being incubated with a recombinant fusion protein of NusA and the SH2 domain of SOCS-2. Significant phosphopeptide/fusion protein interaction was detected with the Tyr(P)⁵⁹⁵ peptide (Fig. 4B), and the specificity of the interaction was confirmed by incubating NusASOCS-2 SH2 protein with either phosphorylated or non-phosphorylated Tyr⁵⁹⁵ peptide, and NusA recombinant protein with Tyr(P)⁵⁹⁵ peptide.

View larger version (24K): [in this window] [in a new window]   Fig. 4.   SOCS-2 interacts with Tyr595 of the GH receptor. A, diagram of the location of tyrosine residues phosphorylated in response to GH and the sequences of the synthesized phosphopeptides. B, immobilized phosphopeptides were incubated with recombinant SOCS-2 SH2 domain protein fused to the NusA protein, washed, separated on SDS-PAGE, and Coomassie-stained. The specificity of the SOCS-2 SH2 domain interaction was tested with non-phosphorylated Tyr595 and NusA with phosphorylated Tyr595.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The observation that mice transgenically overexpressing SOCS-2 did not have repressed growth, but rather slightly enhanced growth, is somewhat surprising given the striking gigantism phenotype of SOCS-2^/ mice (12) and implies that SOCS-2 can also have a positive role in GH signaling. The evidence for SOCS-2 playing a positive role was first reported by Adams et al. (18) and later shown by the more detailed experiments by Favre and colleagues (22). This latter study demonstrated that low concentrations of SOCS-2 inhibited growth hormone action, while higher concentrations SOCS-2 enhanced signaling. A similar phenomenon has been observed with SOCS-2 expression and prolactin signaling, but has not been observed for SOCS-1 or SOCS-3 in any cytokine system (27). This observation has in vivo correlates, since at normal physiological levels SOCS-2 is presumed to have a net inhibitory effect, manifest by an increase in signaling in SOCS-2 deficient mice, while the superphysiological levels of SOCS-2 obtained in the present transgenic mice implicate an accentuation of growth hormone signaling.

Several theories might be put forward to explain the dual effect of SOCS-2. First, overexpressed protein might not be completely functional and may act as a dominant negative. This is unlikely given that FLAG-tagged SOCS-2 can inhibit signaling in vitro and can interact with endogenous GH receptors in vivo. An alternative explanation would propose that SOCS-2 binds to different tyrosine-phosphorylated residues with different affinities. Results in this paper suggest that the high affinity binding site within the growth hormone receptor is Tyr⁵⁹⁵. Tyr⁵⁹⁵ has been implicated in negative regulation of signaling since receptors in which this residue is mutated to Phe exhibit enhanced signaling (28). In addition to SOCS-2, the cytoplasmic tyrosine phosphatase, SHP2, has also been shown to interact with Tyr⁵⁹⁵, and this interaction has been assumed to be responsible for attenuating signaling (28). Our data suggest that SOCS-2 may at least in part be responsible for negative regulation of growth hormone signaling through Tyr⁵⁹⁵, and further studies are required to assess the relative importance of SOCS-2 and SHP-2 in regulation of growth hormone signaling.

Interestingly, in vitro studies showed SOCS-3 to be a more profound inhibitor of GH-induced signaling than SOCS-2. SOCS-3 also binds to the cytoplasmic tail of the growth hormone receptor, although its preferred binding site is either Tyr(P)⁴⁸⁷ (21) or Tyr(P)³³² (19). It will be interesting to determine whether SOCS-2 can bind with low affinity to either of these phosphorylated tyrosine residues. If this is the case, then the capacity of SOCS-2 to potentiate signaling may be due to its ability, at high concentrations, to compete with endogenous SOCS-3 for binding to these Tyr sites on the GH receptor. This model is consistent with the in vitro observation that increasing concentrations of SOCS-2 can overcome the effect of exogenous SOCS-1 and SOCS-3 on growth hormone and prolactin signaling (22, 29). Further biochemical analysis of the interaction between individual SOCS proteins and the GH receptor will aid in understanding the physiological mechanisms of growth regulation.

	ACKNOWLEDGEMENTS

We thank Stephen Mihajlovic for excellent histology, Andrea Morcom for animal care, Sally Crane and Janelle Mighall for genotyping, and Frank Talamtes and Jane Visvader for reagents.

	FOOTNOTES

^* This work was supported by the Anti-Cancer Council of Victoria, Melbourne, Australia; AMRAD Operations Pty. Ltd., Melbourne, Australia; the National Health and Medical Research Council, Canberra, Australia; the J. D. and L. Harris Trust; National Institutes of Health Grant CA-22556; and by the Australian Federal Government Cooperative Research Centers Program.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ Supported by an Australian Postdoctoral Research Fellowship from the Australian Research Council. To whom correspondence should be addressed. Tel.: 61-3-9208-4021; Fax: 61-3-9208-4100; E-mail: greenhalgh@wehi.edu.au.

Published, JBC Papers in Press, September 2, 2002, DOI 10.1074/jbc.C200450200

	ABBREVIATIONS

The abbreviations used are: SOCS, suppressor of cytokine signaling; CIS, cytokine-inducible SH2 domain-containing protein; JAK, Janus kinase; STAT, signal transducer and activators of transcription; IGF, insulin-like growth factor; GH, growth hormone; DME, Dulbecco's modified Eagle's medium; MT-PBS, mouse-tonicity phosphate-buffered saline; rh, recombinant human.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

This article has been cited by other articles:

				I. Uyttendaele, I. Lemmens, A. Verhee, A.-S. De Smet, J. Vandekerckhove, D. Lavens, F. Peelman, and J. Tavernier Mammalian Protein-Protein Interaction Trap (MAPPIT) Analysis of STAT5, CIS, and SOCS2 Interactions with the Growth Hormone Receptor Mol. Endocrinol., November 1, 2007; 21(11): 2821 - 2831. [Abstract] [Full Text] [PDF]

				J. Piessevaux, D. Lavens, T. Montoye, J. Wauman, D. Catteeuw, J. Vandekerckhove, D. Belsham, F. Peelman, and J. Tavernier Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling J. Biol. Chem., November 3, 2006; 281(44): 32953 - 32966. [Abstract] [Full Text] [PDF]

				A M Solomon and P M G Bouloux Modifying muscle mass - the endocrine perspective. J. Endocrinol., November 1, 2006; 191(2): 349 - 360. [Abstract] [Full Text] [PDF]

				S. Gentili, J. S. Schwartz, M. J. Waters, and I. C. McMillen Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1399 - R1405. [Abstract] [Full Text] [PDF]

				D. Lavens, T. Montoye, J. Piessevaux, L. Zabeau, J. Vandekerckhove, K. Gevaert, W. Becker, S. Eyckerman, and J. Tavernier A complex interaction pattern of CIS and SOCS2 with the leptin receptor J. Cell Sci., June 1, 2006; 119(11): 2214 - 2224. [Abstract] [Full Text] [PDF]

				Z. Chen, A. Laurence, Y. Kanno, M. Pacher-Zavisin, B.-M. Zhu, C. Tato, A. Yoshimura, L. Hennighausen, and J. J. O'Shea Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells PNAS, May 23, 2006; 103(21): 8137 - 8142. [Abstract] [Full Text] [PDF]

				C. Z. Michaylira, N. M. Ramocki, J. G. Simmons, C. K. Tanner, K. K. McNaughton, J. T. Woosley, C. J. Greenhalgh, and P. K. Lund Haplotype Insufficiency for Suppressor of Cytokine Signaling-2 Enhances Intestinal Growth and Promotes Polyp Formation in Growth Hormone-Transgenic Mice Endocrinology, April 1, 2006; 147(4): 1632 - 1641. [Abstract] [Full Text] [PDF]

				A. Flores-Morales, C. J. Greenhalgh, G. Norstedt, and E. Rico-Bautista Negative Regulation of Growth Hormone Receptor Signaling Mol. Endocrinol., February 1, 2006; 20(2): 241 - 253. [Abstract] [Full Text] [PDF]

				J G Miquet, A I Sotelo, F P Dominici, M S Bonkowski, A Bartke, and D Turyn Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance J. Endocrinol., December 1, 2005; 187(3): 387 - 397. [Abstract] [Full Text] [PDF]

				J. G. Miquet, A. I. Sotelo, A. Bartke, and D. Turyn Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E600 - E607. [Abstract] [Full Text] [PDF]

				S. Fruchtman, J. G. Simmons, C. Z. Michaylira, M. E. Miller, C. J. Greenhalgh, D. M. Ney, and P. K. Lund Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells Am J Physiol Gastrointest Liver Physiol, August 1, 2005; 289(2): G342 - G350. [Abstract] [Full Text] [PDF]

				E. E. Spangenburg SOCS-3 Induces Myoblast Differentiation J. Biol. Chem., March 18, 2005; 280(11): 10749 - 10758. [Abstract] [Full Text] [PDF]

				F. Haddad, F. Zaldivar, D. M. Cooper, and G. R. Adams IL-6-induced skeletal muscle atrophy J Appl Physiol, March 1, 2005; 98(3): 911 - 917. [Abstract] [Full Text] [PDF]

				D. R. Boverhof, E. Tam, A. S. Harney, R. B. Crawford, N. E. Kaminski, and T. R. Zacharewski 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Suppressor of Cytokine Signaling 2 in Murine B Cells Mol. Pharmacol., December 1, 2004; 66(6): 1662 - 1670. [Abstract] [Full Text] [PDF]

				K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho Estrogen Regulation of Growth Hormone Action Endocr. Rev., October 1, 2004; 25(5): 693 - 721. [Abstract] [Full Text] [PDF]

				J. Rieusset, J. Seydoux, S. I. Anghel, P. Escher, L. Michalik, N. Soon Tan, D. Metzger, P. Chambon, W. Wahli, and B. Desvergne Altered Growth in Male Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Heterozygous Mice: Involvement of PPAR{gamma} in a Negative Feedback Regulation of Growth Hormone Action Mol. Endocrinol., October 1, 2004; 18(10): 2363 - 2377. [Abstract] [Full Text] [PDF]

				L. Li, L. M. Gronning, P. O. Anderson, S. Li, K. Edvardsen, J. Johnston, D. Kioussis, P. R. Shepherd, and P. Wang Insulin Induces SOCS-6 Expression and Its Binding to the p85 Monomer of Phosphoinositide 3-Kinase, Resulting in Improvement in Glucose Metabolism J. Biol. Chem., August 13, 2004; 279(33): 34107 - 34114. [Abstract] [Full Text] [PDF]

				N. Sizemore, A. Agarwal, K. Das, N. Lerner, M. Sulak, S. Rani, R. Ransohoff, D. Shultz, and G. R. Stark Inhibitor of {kappa}B kinase is required to activate a subset of interferon {gamma}-stimulated genes PNAS, May 25, 2004; 101(21): 7994 - 7998. [Abstract] [Full Text] [PDF]

				Y. Goldshmit, C. E. Walters, H. J. Scott, C. J. Greenhalgh, and A. M. Turnley SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation J. Biol. Chem., April 16, 2004; 279(16): 16349 - 16355. [Abstract] [Full Text] [PDF]

				A. Yoshimura, H. M. M. Ohishi, D. Aki, and T. Hanada Regulation of TLR signaling and inflammation by SOCS family proteins J. Leukoc. Biol., March 1, 2004; 75(3): 422 - 427. [Abstract] [Full Text] [PDF]

				S. Wormald and D. J. Hilton Inhibitors of Cytokine Signal Transduction J. Biol. Chem., January 9, 2004; 279(2): 821 - 824. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 277/43/40181    most recent C200450200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Greenhalgh, C. J. Articles by Hilton, D. J. Search for Related Content PubMed PubMed Citation Articles by Greenhalgh, C. J. Articles by Hilton, D. J.