SOCS2 negatively regulates growth hormone action in vitro and in vivo

Greenhalgh, Christopher J.; Rico-Bautista, Elizabeth; Lorentzon, Mattias; Thaus, Anne L.; Morgan, Phillip O.; Willson, Tracy A.; Zervoudakis, Panagiota; Metcalf, Donald; Street, Ian H.; Nicola, Nicos A.; Nash, Andrew D.; Fabri, Louis; Norstedt, Gunnar; Ohlsson, Claes; Flores‐Morales, Amilcar; Alexander, Warren S.; Hilton, Douglas J.

doi:10.1172/jci22710

Cited by 83 publications

(68 citation statements)

References 63 publications

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“…We did not find a direct relationship of SOCS2 with IL6 concentration in placental lysates, and must therefore hypothesise SOCS2 activation by a different mechanism; however, SOCS2 could certainly play an important role in both insulin action through a direct action on the IR or IRS1 (20,29,30), and indirectly by inhibiting the GH receptor (31). GH action is in fact recognised as an important factor regulating insulin sensitivity (32).…”

Section: Discussionmentioning

confidence: 67%

Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

Street

Viani²,

Ziveri³

et al. 2011

European Journal of Endocrinology

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Objective: Intra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth. Design and methods: Whole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits. Results: The amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth. Conclusions: IR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown.

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Section: Discussionmentioning

confidence: 67%

Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

Street

Viani²,

Ziveri³

et al. 2011

European Journal of Endocrinology

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“…Considerable evidence demonstrates that SOCS2 limits the trophic actions of GH. This includes a body overgrowth phenotype in SOCS2 null mice and observations that GH-deficient SOCS2 null mice show enhanced growth responses to exogenous GH (15). Our recent findings that haplotype insufficiency for SOCS2 enhances the effects of a GH transgene on intestinal growth and promotes polyp formation in GH transgenics provide new evidence that SOCS2 limits GH action in the intestine (33).…”

mentioning

confidence: 86%

Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo

Michaylira

Simmons²,

Ramocki³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Suppressors of cytokine signaling (SOCS) typically limit cytokine receptor signaling via the JAK-STAT pathway. Considerable evidence demonstrates that SOCS2 limits growth hormone (GH) action on body and organ growth. Biochemical evidence that SOCS2 binds to the IGF-I receptor (IGF-IR) supports the novel possibility that SOCS2 limits IGF-I action. The current study tested the hypothesis that SOCS2 normally limits basal or IGF-I-induced intestinal growth and limits IGF-IR signaling in intestinal epithelial cells. Intestinal growth was assessed in mice homozygous for SOCS2 gene deletion (SOCS2 null) and wild-type (WT) littermates at different ages and in response to infused IGF-I or vehicle or EGF and vehicle. The effects of SOCS2 on IGF-IR signaling were examined in ex vivo cultures of SOCS2 null and WT intestine and Caco-2 cells. Compared with WT, SOCS2 null mice showed significantly enhanced small intestine and colon growth, mucosal mass, and crypt cell proliferation and decreases in radiation-induced crypt apoptosis in jejunum. SOCS2 null mice showed significantly greater growth responses to IGF-I in small intestine and colon. IGF-I-stimulated activation of IGF-IR and downstream signaling intermediates were enhanced in the intestine of SOCS2 null mice and were decreased by SOCS2 overexpression in Caco-2 cells. SOCS2 bound directly to the endogenous IGF-IR in Caco-2 cells. The intestine of SOCS2 null mice also showed enhanced growth responses to infused EGF. We conclude that SOCS2 normally limits basal and IGF-I- and EGF-induced intestinal growth in vivo and has novel inhibitory effects on the IGF-IR tyrosine kinase pathway in intestinal epithelial cells.

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“…SOCS2 deficient mice display about 50% increased body size primarily due to the loss of negative regulation of growth hormone (GH) receptor function [42]. SOCS2 negatively regulates the GH receptor through ubiquitination-dependent degradation [43].…”

Section: Socs2mentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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SOCS2 negatively regulates growth hormone action in vitro and in vivo

Cited by 83 publications

References 63 publications

Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth

Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo

SOCS proteins in regulation of receptor tyrosine kinase signaling

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