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Claude Haan - One of the best experts on this subject based on the ideXlab platform.
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jaks and Cytokine Receptors an intimate relationship
Biochemical Pharmacology, 2006Co-Authors: Claude Haan, Stephanie Kreis, Christiane Margue, Iris BehrmannAbstract:Abstract Most Cytokine Receptors lack intrinsic kinase activity and many of them signal via Janus kinases (Jaks). These tyrosine kinases are associated with Cytokine receptor subunits, they become activated upon receptor triggering and subsequently activate downstream signalling events, e.g. the phosphorylation of STAT transcription factors. The successful interplay between Cytokines, their Receptors and the connected Jaks not only determines signalling competence but is also vital for intracellular traffic, stability, and fate of the cognate Receptors. Here, we will discuss underlying mechanisms as well as some structural features with a focus on Jak1 and two of the signal transducing receptor subunits of interleukin (IL)-6 type Cytokines, gp130 and OSMR. Regions that are critically involved in Jak-binding have been identified for many Cytokine receptor subunits. In most cases the membrane-proximal parts comprising the box1 and box2 regions within the receptor are involved in this association while, within Jaks, the N-terminal FERM domain, possibly together with the SH2-like domain, are pivotal for binding to the relevant Receptors. The exclusive membrane localisation of Jaks depends on their ability to associate with Cytokine Receptors. For gp130 and Jak1, it was shown that the Cytokine receptor/Jak complex can be regarded as a receptor tyrosine kinase since both molecules have the same diffusion dynamics and are virtually undissociable. Furthermore, Jaks take an active role in the regulation of the surface expression of at least some Cytokine Receptors, including the OSMR and this may provide a quality control mechanism ensuring that only signalling-competent Receptors (i.e. those with an associated Jak) would be enriched at the cell surface.
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janus kinase jak subcellular localization revisited the exclusive membrane localization of endogenous janus kinase 1 by Cytokine receptor interaction uncovers the jak receptor complex to be equivalent to a receptor tyrosine kinase
Journal of Biological Chemistry, 2004Co-Authors: Iris Behrmann, Tanja Smyczek, Peter C Heinrich, Hildegard Schmitzvan De Leur, Waraporn Komyod, Bernd Giese, Gerhard Mullernewen, Serge Haan, Claude HaanAbstract:Abstract The Janus kinases are considered to be cytoplasmic kinases that constitutively associate with the cytoplasmic region of Cytokine Receptors, and the Janus kinases (Jaks) are crucial for Cytokine signal transduction. We investigated Jak1 localization using subcellular fractionation techniques and fluorescence microscopy (immunofluorescence and yellow fluorescent protein-tagged Jaks). In the different experimental approaches we found Jak1 (as well as Jak2 and Tyk2) predominantly located at membranes. In contrast to previous reports we did not observe Jak proteins in significant amounts within the nucleus or in the cytoplasm. The cytoplasmic localization observed for the Jak1 mutant L80A/Y81A, which is unable to associate with Cytokine Receptors, indicates that Jak1 does not have a strong intrinsic membrane binding potential and that only receptor binding is crucial for the membrane recruitment. Finally we show that Jak1 remains a membrane-localized protein after Cytokine stimulation. These data strongly support the hypothesis that Cytokine receptor·Janus kinase complexes can be regarded as receptor tyrosine kinases.
Iris Behrmann - One of the best experts on this subject based on the ideXlab platform.
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jaks and Cytokine Receptors an intimate relationship
Biochemical Pharmacology, 2006Co-Authors: Claude Haan, Stephanie Kreis, Christiane Margue, Iris BehrmannAbstract:Abstract Most Cytokine Receptors lack intrinsic kinase activity and many of them signal via Janus kinases (Jaks). These tyrosine kinases are associated with Cytokine receptor subunits, they become activated upon receptor triggering and subsequently activate downstream signalling events, e.g. the phosphorylation of STAT transcription factors. The successful interplay between Cytokines, their Receptors and the connected Jaks not only determines signalling competence but is also vital for intracellular traffic, stability, and fate of the cognate Receptors. Here, we will discuss underlying mechanisms as well as some structural features with a focus on Jak1 and two of the signal transducing receptor subunits of interleukin (IL)-6 type Cytokines, gp130 and OSMR. Regions that are critically involved in Jak-binding have been identified for many Cytokine receptor subunits. In most cases the membrane-proximal parts comprising the box1 and box2 regions within the receptor are involved in this association while, within Jaks, the N-terminal FERM domain, possibly together with the SH2-like domain, are pivotal for binding to the relevant Receptors. The exclusive membrane localisation of Jaks depends on their ability to associate with Cytokine Receptors. For gp130 and Jak1, it was shown that the Cytokine receptor/Jak complex can be regarded as a receptor tyrosine kinase since both molecules have the same diffusion dynamics and are virtually undissociable. Furthermore, Jaks take an active role in the regulation of the surface expression of at least some Cytokine Receptors, including the OSMR and this may provide a quality control mechanism ensuring that only signalling-competent Receptors (i.e. those with an associated Jak) would be enriched at the cell surface.
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janus kinase jak subcellular localization revisited the exclusive membrane localization of endogenous janus kinase 1 by Cytokine receptor interaction uncovers the jak receptor complex to be equivalent to a receptor tyrosine kinase
Journal of Biological Chemistry, 2004Co-Authors: Iris Behrmann, Tanja Smyczek, Peter C Heinrich, Hildegard Schmitzvan De Leur, Waraporn Komyod, Bernd Giese, Gerhard Mullernewen, Serge Haan, Claude HaanAbstract:Abstract The Janus kinases are considered to be cytoplasmic kinases that constitutively associate with the cytoplasmic region of Cytokine Receptors, and the Janus kinases (Jaks) are crucial for Cytokine signal transduction. We investigated Jak1 localization using subcellular fractionation techniques and fluorescence microscopy (immunofluorescence and yellow fluorescent protein-tagged Jaks). In the different experimental approaches we found Jak1 (as well as Jak2 and Tyk2) predominantly located at membranes. In contrast to previous reports we did not observe Jak proteins in significant amounts within the nucleus or in the cytoplasm. The cytoplasmic localization observed for the Jak1 mutant L80A/Y81A, which is unable to associate with Cytokine Receptors, indicates that Jak1 does not have a strong intrinsic membrane binding potential and that only receptor binding is crucial for the membrane recruitment. Finally we show that Jak1 remains a membrane-localized protein after Cytokine stimulation. These data strongly support the hypothesis that Cytokine receptor·Janus kinase complexes can be regarded as receptor tyrosine kinases.
Vickie E. Baracos - One of the best experts on this subject based on the ideXlab platform.
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Cytokines and endotoxin induce Cytokine Receptors in skeletal muscle.
American Journal of Physiology-endocrinology and Metabolism, 2000Co-Authors: Yan Zhang, Geneviève Pilon, André Marette, Vickie E. BaracosAbstract:Proinflammatory Cytokines are important factors in the regulation of diverse aspects of skeletal muscle function; however, the muscle Cytokine Receptors mediating these functions are uncharacterize...
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Cytokines and endotoxin induce Cytokine Receptors in skeletal muscle.
American Journal of Physiology Endocrinology and Metabolism, 2000Co-Authors: Yong Zhang, Geneviève Pilon, André Marette, Vickie E. BaracosAbstract:Proinflammatory Cytokines are important factors in the regulation of diverse aspects of skeletal muscle function; however, the muscle Cytokine Receptors mediating these functions are uncharacterized. Binding kinetics (dissociation constant = 39+/-4.7 x 10(-9) M, maximal binding = 3.5+/-0.23 x 10(-12) mol/mg membrane protein) of muscle tumor necrosis factor (TNF) Receptors were obtained. Skeletal muscle was found to express mRNAs encoding interleukin-1 type I and II Receptors, interleukin-6 receptor (IL-6R), and interferon-gamma receptor by RT-PCR, but these Receptors were below limits of detection of ligand-binding assay (> or =1 fmol binding sites/mg protein). Twenty-four hours after intraperitoneal administration of endotoxin to rats, TNF receptor type II (TNFRII) and IL-6R mRNA were increased in skeletal muscle (P
Thomas Pollmächer - One of the best experts on this subject based on the ideXlab platform.
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plasma levels of Cytokines and soluble Cytokine Receptors in psychiatric patients upon hospital admission effects of confounding factors and diagnosis
Journal of Psychiatric Research, 1999Co-Authors: Monika Haack, T. Fenzel, Thomas Kraus, Andreas Schuld, D Hinzeselch, M Kuhn, Thomas PollmächerAbstract:Abstract It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of Cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of Cytokines and soluble Cytokine Receptors in psychiatric patients ( N =361) upon hospital admission and compared the results to those obtained in healthy controls ( N =64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), soluble TNF Receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or Cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-α, sTNF-R p75, IL-6) or benzodiazepines (TNF-α, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-α and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned Cytokines and Cytokine Receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.
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Plasma Levels of Cytokines and Soluble Cytokine Receptors During Treatment With Haloperidol
American Journal of Psychiatry, 1997Co-Authors: Thomas Pollmächer, Dunja Hinze-selch, T. Fenzel, Thomas Kraus, Andreas Schuld, Janet MullingtonAbstract:OBJECTIVE: Clozapine increases the levels of Cytokines and soluble Cytokine Receptors. The authors investigated whether haloperidol has similar effects. METHOD: Rectal temperature, white blood cell counts, and plasma levels of Cytokines and soluble Cytokine Receptors were assessed before and during 6 weeks of haloperidol treatment in 10 psychiatric patients. RESULTS: Haloperidol at mean doses of 7.0 mg/day (SD=3.4), 6.9 mg/day (SD=3.4), and 5.0 mg/day (SD=3.1) at the end of the 1st, 2nd, and 6th weeks of treatment, respectively, did not affect rectal temperature, white blood cell counts, or plasma level of interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor—alpha (TNF-α), soluble TNF receptor p55 or p75, or soluble interleukin-2 receptor. CONCLUSIONS: Haloperidol is unlikely to confound the results of studies investigating disease-related alterations in the levels of a broad range of Cytokines and soluble Cytokine Receptors in schizophrenia. (Am J Psychiatry 1997; 154:1763–1765)
Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of the changes in circulating Cytokines soluble Cytokine Receptors and white blood cell subset counts in patients with rheumatoid arthritis ra after monoclonal anti tnfα antibody therapy
Journal of Clinical Immunology, 1999Co-Authors: Shiro Ohshima, Yukihiko Saeki, Toru Mima, Mitsuko Sasai, Katsuhiro Nishioka, Hiroshi Ishida, Masatoshi Shimizu, Masaki Suemura, Richard Mccloskey, Tadamitsu KishimotoAbstract:To investigate the mechanism of the long-lasting efficacy of chimeric monoclonal anti-TNFα antibody (cA2) therapy for rheumatoid arthritis (RA), eight patients with refractory RA were treated with a single infusion of cA2 and the changes in circulating Cytokines (IL-1, IL-6, TNFα, and IL-10), soluble Cytokine Receptors (TNF-RI, RII, and sIL-6R) and peripheral white blood cell (WBC) subset counts were followed up long-term (12 weeks) after cA2 therapy in them. Significant clinical responses (>20% improvement according to Paulus' criteria) were observed just after cA2 infusion and lasted more than 4 weeks in all patients, as reported elsewhere. Moreover, five of the eight patients showed prolonged clinical responses (>12 weeks). The elevated serum IL-6 and sTNF-RI (or RII) levels before treatment rapidly decreased after treatment. The serum IL-10 levels also significantly elevated before treatment. The elevations of serum IL-10 levels were augmented after treatment and stayed higher than the baseline in four patients with prolonged clinical responses. No significant TNFα, IL-1α and -β, or sIL-6R were detected in the sera of the patients before treatment and during the whole study period. On the other hand, peripheral lymphocytes as well as total WBC and neutrophils increased for 4 weeks after treatment. However, thereafter, only the lymphocyte count decreased gradually and stayed below the baseline long-term (12 weeks). FACS analysis revealed the predominance of T lymphocytes in the decrease in lymphocyte counts. These results suggest that the augmentation of IL-10 production and the decrease in T cells might partly contribute to the long-lasting efficacy of cA2 treatment in RA.
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Cytokine Receptors and signal transduction
The FASEB Journal, 1992Co-Authors: Tetsuya Taga, Tadamitsu KishimotoAbstract:Most of the recently cloned Cytokine Receptors that operate in the immune and hematopoietic systems contain no tyrosine kinase domains in their cytoplasmic regions, unlike the family of growth factor Receptors defined earlier. However, they can be assigned to several new types of receptor families based on structural similarities among them. It is characteristic of these Receptors that many of them require a receptor-associated molecule in order to achieve high-affinity ligand binding and/or transmission of cytoplasmic signals. Receptor-associated molecules have been found that transduce cytoplasmic signals and are shared by different Cytokine Receptors. Phosphorylation of the Receptors and of various cytoplasmic proteins after ligand stimulation seems to be a common event in Cytokine systems. Insight into the pleiotropic and redundant nature of Cytokine action is provided by the discovery of several new Cytokine receptor families and of shared signal transduction molecules and by the idea that several cy...
