Role of the Cytokine-inducible SH2 Protein CIS in Desensitization of STAT5b Signaling by Continuous Growth Hormone

Ram, Prabha A.; Waxman, David J.

doi:10.1074/jbc.m004755200

Cited by 113 publications

(119 citation statements)

References 57 publications

(85 reference statements)

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“…CIS is an effective and specific negative regulator of GH-induced STAT5 activity. It interacts with tyrosine phosphorylated residues on the GHR cytoplasmic tail, thereby masking STAT5 recruitment sites and inhibiting its phosphorylation and activation (Ram & Waxman 2000, Inagaki-Ohara et al 2003, Greenhalgh & Alexander 2004. The significant reduction in the level of CIS in Ames dwarf mice described in the present paper and the dramatic increase previously found for GH-overexpressing mice correlate with the levels of GH displayed by these mice, suggesting a strong regulation of this protein by GH in vivo (Fig.…”

Section: Discussionsupporting

confidence: 68%

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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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Section: Discussionsupporting

confidence: 68%

“…CIS acts as a negative modulator by competing with STAT5 for common phosphotyrosine-binding sites on the GHR intracellular domain (Ram & Waxman 2000). SH2-B protein content and membrane-association were also increased in GH-overexpressing transgenic mice, which may be implicated in JAK2 desensitization (Miquet et al 2005).…”

Section: Introductionmentioning

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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“…This has been shown to substantially decrease cell sensitivity to the relevant cytokine (Ram and Waxman, 2000;Tauchi et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

“…Suppressors of cytokine signalling proteins are rapidly induced by activated STATs and act to block the cytokine signal either by direct inhibition of JAKs (SOCS-1), by binding to tyrosine phosphorylated receptor so as to exclude binding of other SH2 and PTB domain-containing signalling proteins such as STATs (CIS), or by both mechanisms (SOCS-3) (Ram and Waxman, 1999). SOCS proteins are also able to accelerate proteasome-mediated destruction of the activated cytokine -receptor complex (Ram and Waxman, 2000;Kamizono et al, 2001), particularly in the case of CIS. These inhibitory regulators not only attenuate the signal from the activated cytokine receptor itself, but can also decrease cell sensitivity to other cytokines and hormones, such as insulin (Emanuelli et al, 2000).…”

mentioning

confidence: 99%

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma

et al. 2003

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Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1 -3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1 -3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

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“…Once induced, the SOCS3/CIS families are major inhibitors of GHR signaling (Adams et al 1998, Hansen et al 1999, Ram & Waxman 1999, Ronn et al 2002, Flores-Morales et al 2006, not only by blocking STAT phosphorylation but also by targeting the GHR for ubiquitination and subsequent degradation by the proteosome (Kamura et al 1998, Zhang et al 1999, Ram & Waxman 2000, Kile & Alexander 2001, Wormald & Hilton 2004, Flores-Morales et al 2006. Whether the SOCS-ubiquitinproteosome pathway is active in the FH remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Developmental changes in the human GH receptor and its signal transduction pathways

Kenth

Mergelas²,

Goodyer

2008

Journal of Endocrinology

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We previously reported the presence of functional human GH receptors (hGHRs) in the human fetal hepatocyte (FH) as early as the first trimester. Interestingly, fetal serum levels of hGH are in the acromegalic range, yet certain hGH-dependent factors are expressed at very low levels (IGF-I, IGF-binding protein-3), suggesting that fetal liver has limited responsiveness to hGH. To determine whether this is due to the fetal tissue levels of hGHR or factors in the hGH/hGHR axis that might influence hGHR function, we compared hGHR isoforms and downstream signaling proteins in FH versus human adult liver (HAL). Immunoprecipitation/immunoblotting (IB) analyses found similar precursor and mature hGHR forms while RT-PCR assays of truncated (T) hGHR 1-279 , dominant negative for the full-length (FL) receptor, showed similar T/FL mRNA ratios in FH and HAL. IB demonstrated that Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT(1, 3, 5A/B)), and suppressors of cytokine signaling (SOCS(1, 2, 3, cytokineinducible SH2-containing protein (CIS))) proteins were detectable in all FH and HAL tested (12 weeks of fetal age to 60 years); the levels were similar (STAT5B) or lower (JAK2/STAT1/STAT3/STAT5A: 38-53%, SOCS/CIS: 58-76%) in FH compared with HAL. Our studies to date demonstrate that, during hepatocyte development, hGHR levels are lower in the fetal cells but the hGHR isoforms, including the relative amount of truncated versus FL, remain unchanged. The JAK2/STAT/SOCS signaling molecules are present in the FH as early as the first trimester. However, they are generally at !50% level in postnatal liver. These data suggest that low expression of both hGHR and major hGHR signaling components may explain the limited responsiveness of the fetal cells to the high circulating levels of hGH.

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Role of the Cytokine-inducible SH2 Protein CIS in Desensitization of STAT5b Signaling by Continuous Growth Hormone

Cited by 113 publications

References 57 publications

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

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

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma

Developmental changes in the human GH receptor and its signal transduction pathways

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