scholarly journals Structure−Affinity Relationships of Glutamine Mimics Incorporated into Phosphopeptides Targeted to the SH2 Domain of Signal Transducer and Activator of Transcription 3

2009 ◽  
Vol 52 (19) ◽  
pp. 6126-6141 ◽  
Author(s):  
Pijus K. Mandal ◽  
Zhiyong Ren ◽  
Xiaomin Chen ◽  
Chiyi Xiong ◽  
John S. McMurray
Keyword(s):  
Sh2 Domain ◽  
Signal Transducer ◽  
Transcription 3

scholarly journals Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 867-880 ◽  
Author(s):  
Rula A. Abbud ◽  
Robert Kelleher ◽  
Shlomo Melmed
Keyword(s):  
Transcription Factors ◽  
Leukemia Inhibitory Factor ◽  
Expression Profiles ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Induced Expression ◽  
Transcription 3

Abstract Leukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke’s cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH3) cells. In addition to genes known to respond to LIF in corticotrope cells [e.g. suppressor of cytokine signaling-3 (SOCS-3), signal transducer and activator of transcription-3, SH2 domain-containing tyrosine phosphatase-1, and proopiomelanocortin (POMC)], corticotrope-specific changes were also observed for genes involved in glycolysis and gluconeogenesis, transcription factors, signaling molecules, and expressed sequence tags. Two transcription factors identified, CCAAT/enhancer-binding protein β (C/EBPβ) and glial cell-derived neurotrophic factor (GDNF)-inducible factor (GIF), dose-dependently induced expression of the rat POMC promoter when overexpressed in AtT-20 cells. LIF further induced POMC transcription with C/EBPβ, but not with GIF. C/EBPβ also induced expression of the SOCS-3 promoter that was further enhanced by cotreatment with LIF. However, GIF did not affect SOCS-3 expression. These results indicate that C/EBPβ and GIF are downstream effectors of LIF corticotrope action. LIF also stimulates the expression of inhibitors of its actions, such as SOCS-3 and SH2 domain-containing tyrosine phosphatase-1. α2-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFβ/bone morphogenic protein signaling, was induced by LIF in a signal transducer and activator of transcription-3-dependent fashion. Pretreatment with AHSG/fetuin blocked LIF-induced expression of the POMC promoter independently of SOCS-3. Thus, using GeneChips, C/EBPβ and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.

scholarly journals Feedback Inhibition of Leptin Receptor/Jak2 Signaling via Tyr1138 of the Leptin Receptor and Suppressor of Cytokine Signaling 3

2005 ◽  
Vol 19 (4) ◽  
pp. 925-938 ◽  
Author(s):  
Sarah L. Dunn ◽  
Marie Björnholm ◽  
Sarah H. Bates ◽  
Zhibin Chen ◽  
Matthew Seifert ◽  
...  
Keyword(s):  
Rna Interference ◽  
Leptin Receptor ◽  
Feedback Inhibition ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity ◽  
Transcription 3

Abstract Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

scholarly journals Analysis of Stat3 (signal transducer and activator of transcription 3) dimerization by fluorescence resonance energy transfer in living cells

2004 ◽  
Vol 377 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Antje K. KRETZSCHMAR ◽  
Michaela C. DINGER ◽  
Christian HENZE ◽  
Katja BROCKE-HEIDRICH ◽  
Friedemann HORN
Keyword(s):  
Energy Transfer ◽  
Tyrosine Phosphorylation ◽  
Fluorescence Resonance Energy Transfer ◽  
Fusion Proteins ◽  
Fluorescent Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Sh2 Domain ◽  
Signal Transducer ◽  
Transcription 3

Signal transducer and activator of transcription 3 (Stat3) dimerization is commonly thought to be triggered by its tyrosine phosphorylation in response to interleukin-6 (IL-6) or other cytokines. Accumulating evidence from in vitro studies, however, suggests that cytoplasmic Stat3 may be associated with high-molecular-mass protein complexes and/or dimerize prior to its activation. To directly study Stat3 dimerization and subcellular localization upon cytokine stimulation, we used live-cell fluorescence spectroscopy and imaging microscopy combined with fluorescence resonance energy transfer (FRET). Stat3 fusion proteins with spectral variants of green fluorescent protein (GFP), cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) were constructed and expressed in human hepatoma cells (HepG2) and human embryonic kidney cells (HEK-293). Like wild-type Stat3, the fusion proteins redistributed from a preferentially cytoplasmic to nuclear localization upon IL-6 stimulation and supported IL-6-dependent target gene expression. FRET studies in cells co-expressing Stat3–CFP and Stat3–YFP demonstrated that Stat3 dimers exist in the absence of tyrosine phosphorylation. IL-6 induced a 2-fold increase of this basal FRET signal, indicating that tyrosine phosphorylation either increases the dimer/monomer ratio of Stat3 or induces a conformational change of the dimer yielding a higher FRET efficiency. Studies using a mutated Stat3 with a non-functional src-homology 2 (SH2) domain showed that the SH2 domain is essential for dimer formation of phosphorylated as well as non-phosphorylated Stat3. Furthermore, our data show that visualization of normalized FRET signals allow insights into the spatiotemporal dynamics of Stat3 signal transduction.

scholarly journals Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

2011 ◽  
Vol 54 (10) ◽  
pp. 3549-3563 ◽  
Author(s):  
Pijus K. Mandal ◽  
Fengqin Gao ◽  
Zhen Lu ◽  
Zhiyong Ren ◽  
Rajagopal Ramesh ◽  
...  
Keyword(s):  
Sh2 Domain ◽  
Signal Transducer ◽  
Src Homology 2 ◽  
Src Homology ◽  
Transcription 3

scholarly journals Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

2011 ◽  
Vol 208 (7) ◽  
pp. 1359-1366 ◽  
Author(s):  
Camilla Pilati ◽  
Mohamed Amessou ◽  
Michel P. Bihl ◽  
Charles Balabaud ◽  
Jeanne Tran Van Nhieu ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Liver Tumors ◽  
Sh2 Domain ◽  
Signal Transducer ◽  
Somatic Signal ◽  
First Time ◽  
Transcription 3 ◽  
Stat3 Mutations ◽  
Hepatocellular Adenomas

Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.

Hypoxia is a potent inducer of the iron masterswitch hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

2017 ◽  
Author(s):  
I Silva ◽  
V Rausch ◽  
T Peccerella ◽  
G Millonig ◽  
HK Seitz ◽  
...  
Keyword(s):  
Signal Transducer ◽  
Potent Inducer ◽  
Transcription 3
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