Dual effects of suppressor of cytokine signaling (SOCS‐2) on growth hormone signal transduction

Favre, H.; Benhamou, Aurélie; Finidori, J.; Kelly, Paul A.; Edery, Marc

doi:10.1016/s0014-5793(99)00681-x

Cited by 117 publications

(119 citation statements)

References 23 publications

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“…However, it is likely that in transgenic mice overexpressing SOCS2, the observed increased growth is the result of a SOCS2 blockade of signaling by the more GH potent inhibitors, SOCS1 and SOCS3, at the GHR tyrosine motifs. (35,65,66) These observations indicate that SOCS1 and a lack of GH effect on metatarsal growth. (43,44,(54)(55)(56)68) However, Scheven and Hamilton did report GH stimulatory effects on metatarsal length, which is in contrast to the data of this current study.…”

Section: Discussionmentioning

confidence: 77%

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Pass

MacRae

Huesa

et al. 2012

Journal of Bone and Mineral Research

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Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2 À/À mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain-and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2 À/À chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2À/À embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2 À/À 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2 À/À mouse represents a valid model for studying the local effects of GH on bone growth. ß

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Section: Discussionmentioning

confidence: 77%

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Pass

MacRae

Huesa

et al. 2012

Journal of Bone and Mineral Research

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“…Surprisingly, SOCS2 transgenic mice also show an increase in body weight, suggesting a dual role for SOCS2 in the GH signaling cascade. This is supported by in vitro experiments, in which only low-to-intermediate levels of SOCS2 show inhibitory action on GH signaling, whereas high levels of ectopic SOCS2 expression even increase STAT5 activation in response to GH stimulation (20,21). SOCS2 expression is induced by a number of different cytokines and hormones in many cell types (22).…”

Section: Endritic Cells (Dcs) Play Important Roles In Immune Recognmentioning

confidence: 85%

Suppressor of Cytokine Signaling 2 Is a Feedback Inhibitor of TLR-Induced Activation in Human Monocyte-Derived Dendritic Cells

Posselt

Schwarz

Duschl

et al. 2011

The Journal of Immunology

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Dendritic cells (DCs) are key players in initiating and directing the immune response. Therefore, their activation state and functional differentiation need to be tightly controlled. The activating stimuli and their signaling networks have long been an area of focus in DC research. Recent investigations have also shed light on the mechanisms of counterregulation and fine-tuning of DC functions. One class of proteins involved in these processes is the family of suppressors of cytokine signaling (SOCS), whose members were originally described as feedback inhibitors of cytokine-induced JAK/STAT signaling. Essential roles in DC function have been assigned to SOCS1 and SOCS3. In this article, we show that SOCS2 also is involved in DC regulation. In human and in murine DCs, SOCS2 is a highly TLR-responsive gene, which is expressed in a time-delayed fashion beginning 8 h after TLR ligation. Functionally, silencing of SOCS2 in DCs results in hyperphosphorylation of STAT3 at later time points. As a consequence, SOCS2-deficient DCs secrete increased amounts of the cytokines IL-1β and IL-10, both being transcriptional targets of STAT3. We propose a model in which SOCS2 acts as a negative regulator of TLR-induced DC activation. The delayed expression of SOCS2 provides a mechanism of late-phase counterregulation and limitation of inflammation-driving DC activity.

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“…Until now, there is no conclusive evidence of any physiologic role of SOCS-1 and SOCS-3 in growth control (Greenhalgh & Alexander 2004). Although it was demonstrated that SOCS-2 binds to two phosphorylated tyrosines on the GHR, its mechanism of action (Greenhalgh et al 2005), its actions on GH signaling have been disputed, including positive and inhibitory effects on STAT activation in different models (Favre et al 1999, Greenhalgh et al 2002, 2005. We determined SOCS-1, -2 and -3 in Ames dwarf mice in order to establish the impact of undetectable GH levels on these proteins.…”

Section: Discussionmentioning

confidence: 99%

Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance

Miquet

Sotelo²,

Dominici³

et al. 2005

Journal of Endocrinology

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To investigate the influence of chronic GH deficiency on GH signaling in vivo, we have analyzed Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 5 GH signaling pathway, and its regulation by the suppressors of the cytokine signaling SOCS and by the JAK2-interacting protein SH2-B , in liver of Ames dwarf (Prop1 df /Prop1 df ) mice, which are severely deficient in GH, prolactin and TSH, and of their normal littermates. Prop1 df /Prop1 df mice displayed unaltered GH receptor, JAK2 and STAT5a/b protein levels. No significant differences in the basal tyrosine-phosphorylation levels of JAK2 and STAT5a/b were found between both groups of animals. After in vivo administration of a high GH dose (5 µg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice.However, after stimulation with lower GH doses (50 and 15 ng/g BW) the tyrosine-phosphorylation level of STAT5a/b was higher in dwarf mice. The protein content of CIS, a SOCS protein that inhibits STAT5 signaling, was approximately 80% lower in dwarf mice liver, while SOCS-2 and SOCS-3 levels were unaltered. The content of SH2-B , a modulator of JAK2 activity, was reduced by approximately 30% in dwarf mice, although this was associated with normal JAK2 response to a high GH dose. In summary, Prop1 df /Prop1 df mice display increased hepatic sensitivity to GH, an effect that could be related to the lower abundance of CIS in this tissue. Furthermore, the lower CIS content found in this model of GH deficiency suggests that CIS protein levels are regulated by GH in vivo.

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Dual effects of suppressor of cytokine signaling (SOCS‐2) on growth hormone signal transduction

Cited by 117 publications

References 23 publications

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Suppressor of Cytokine Signaling 2 Is a Feedback Inhibitor of TLR-Induced Activation in Human Monocyte-Derived Dendritic Cells

Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance

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