References of "Schaper, Fred"
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See detailKapitel 34: Mediatoren
Heinrich, Peter C.; Haan, Serge UL; Hermanns, Heike M. et al

in Heinrich, Peter C.; Müller, Matthias; Graeve, Lutz (Eds.) Biochemie und Pathobiochemie (2014)

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See detailKapitel 35: Rezeptoren und ihre Signaltransduktion
Heinrich, Peter C.; Haan, Serge UL; Hermanns, Heike M. et al

in Heinrich, Peter C.; Müller, Matthias; Graeve, Lutz (Eds.) Biochemie und Pathobiochemie (2014)

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See detailJAK2-V617F-induced MAPK activity is regulated by PI3K and acts synergistically with PI3K on the proliferation of JAK2-V617F-positive cells.
Wolf, Alexandra; Eulenfeld, Rene; Gäbler, Karoline UL et al

in JAK-STAT (2013), 2(3), 24574

The identification of a constitutively active JAK2 mutant, namely JAK2-V617F, was a milestone in the understanding of Philadelphia chromosome-negative myeloproliferative neoplasms. The JAK2-V617F mutation ... [more ▼]

The identification of a constitutively active JAK2 mutant, namely JAK2-V617F, was a milestone in the understanding of Philadelphia chromosome-negative myeloproliferative neoplasms. The JAK2-V617F mutation confers cytokine hypersensitivity, constitutive activation of the JAK-STAT pathway, and cytokine-independent growth. In this study we investigated the mechanism of JAK2-V617F-dependent signaling with a special focus on the activation of the MAPK pathway. We observed JAK2-V617F-dependent deregulated activation of the multi-site docking protein Gab1 as indicated by constitutive, PI3K-dependent membrane localization and tyrosine phosphorylation of Gab1. Furthermore, we demonstrate that PI3K signaling regulates MAPK activation in JAK2-V617F-positve cells. This cross-regulation of the MAPK pathway by PI3K affects JAK2-V617F-specific target gene induction, erythroid colony formation, and regulates proliferation of JAK2-V617F-positive patient cells in a synergistically manner. [less ▲]

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See detailKapitel 25: Kommunikation zwischen Zellen: Extrazelluläre Signalmoleküle, Rezeptoren und Signaltransduktion
Heinrich, Peter C.; Haan, Serge UL; Hermanns, Heike M. et al

in Löffler, Georg; Petrides, P. E.; Heinrich, Peter C. (Eds.) Biochemie und Pathobiochemie (2007)

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See detailDeterminants governing the potency of STAT3 activation via the individual STAT3-recruiting motifs of gp130.
Lehmann, Ute; Sommer, Ulrike; Smyczek, Tanya et al

in Cellular Signalling (2006), 18(1), 40-9

In recent years, the elucidation of the structures of many signalling molecules has allowed new insights into the molecular mechanisms that govern signal transduction events. In the field of cytokine ... [more ▼]

In recent years, the elucidation of the structures of many signalling molecules has allowed new insights into the molecular mechanisms that govern signal transduction events. In the field of cytokine signalling, the solved structures of cytokine/receptor complexes and of key components involved in signal transduction such as STAT factors or the tyrosine phosphatase SHP2 have broadened our understanding of the molecular basis of the signalling events and provided key information for the rational design of therapeutic approaches to modulate or block cytokine signal transduction. Unfortunately, no structural data on the intracellular parts of cytokine receptors are available. The exact molecular mechanism underlying one of the first steps in signal transduction, namely the recruitment of signalling components to the cytoplasmic parts of cytokine receptors, remains elusive. Here we investigated possible mechanisms underlying the different potency of the STAT3-activating motifs of gp130 after IL-6 stimulation. Our data indicate that the extent of STAT3 activation by the different receptor motifs is not influenced by structural features such as contacts between the two gp130 chains. In addition, the proximity of the negatively regulating motif around tyrosine Y759 to the different STAT3-recruiting motifs does not seem to be responsible for their differential capacity to activate STAT3. However, the potency of a specific motif to activate STAT3 directly reflects the affinity for the binding of STAT3 to this motif. [less ▲]

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See detailMechanisms of SOCS3 phosphorylation upon interleukin-6 stimulation. Contributions of Src- and receptor-tyrosine kinases.
Sommer, Ulrike; Schmid, Christine; Sobota, Radoslaw M. et al

in Journal of Biological Chemistry (2005), 280(36), 31478-88

The suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine signal transduction. SOCS3 is a key negative regulator of interleuking-6 (IL-6) signal transduction. Furthermore ... [more ▼]

The suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine signal transduction. SOCS3 is a key negative regulator of interleuking-6 (IL-6) signal transduction. Furthermore, SOCS3 was shown to be phosphorylated upon treatment of cells with IL-2, and this has been reported to regulate its function and half-life. We set out to investigate whether SOCS3 phosphorylation may play a role in IL-6 signaling. Tyrosine-phosphorylated SOCS3 was detected upon treatment of mouse embryonic fibroblasts with IL-6. Interestingly, the observed SOCS3 phosphorylation does not require SOCS3 recruitment to phosphotyrosine (Tyr(P)) 759 of gp130, and the kinetics of SOCS3 phosphorylation do not match the activation kinetics of the Janus kinases. This suggests that other kinases may be involved in SOCS3 phosphorylation. Using Src and Janus kinase inhibitors as well as Src kinase-deficient mouse embryonic fibroblasts, we provide evidence that Src kinases, which we found to be constitutively active in these cells, are involved in the phosphorylation of IL-6-induced SOCS3. In addition, we found that receptor-tyrosine kinases such as platelet-derived growth factor receptor or epidermal growth factor receptor can very potently phosphorylate IL-6-induced SOCS3. Taken together, these results suggest that SOCS3 phosphorylation is not a JAK-mediated phenomenon but is dependent on the activity of other kinases such as Src kinases or receptor-tyrosine kinases, which can either be constitutively active or activated by an additional stimulus. [less ▲]

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See detailActivation of STAT3 by IL-6 and IL-10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3.
Niemand, Claudia; Nimmesgern, Ariane; Haan, Serge UL et al

in Journal of immunology (Baltimore, Md. : 1950) (2003), 170(6), 3263-72

On human macrophages IL-10 acts as a more potent anti-inflammatory cytokine than IL-6, although both cytokines signal mainly via activation of the transcription factor STAT3. In this study we compare IL ... [more ▼]

On human macrophages IL-10 acts as a more potent anti-inflammatory cytokine than IL-6, although both cytokines signal mainly via activation of the transcription factor STAT3. In this study we compare IL-10 and IL-6 signaling in primary human macrophages derived from blood monocytes. Pretreatment of macrophages with PMA or the proinflammatory mediators LPS and TNF-alpha blocks IL-6-induced STAT3 activation, whereas IL-10-induced activation of STAT3 remains largely unaffected. Although LPS induces the feedback inhibitor suppressor of cytokine signaling 3 (SOCS3) in macrophages, inhibition of IL-6 signal transduction by LPS occurs rapidly and does not depend on gene transcription. We also found that pretreatment of macrophages with IL-10 inhibits subsequent STAT3 activation by IL-6, whereas IL-10-induced STAT3 activation is not affected by preincubation with IL-6. This cross-inhibition is dependent on active transcription and might therefore be explained by different sensitivities of IL-10 and IL-6 signaling toward the feedback inhibitor SOCS3, which is induced by both cytokines. In contrast to the IL-6 signal transducer gp130, which has been previously shown to recruit SOCS3 to one of its phosphotyrosine residues (Y759), peptide precipitation experiments suggest that SOCS3 does not interact with phosphorylated tyrosine motifs of the IL-10R. Taken together, different sensitivities of IL-10 and IL-6 signaling toward mechanisms that inhibit the Janus kinase/STAT pathway define an important mechanism that contributes to the different anti-inflammatory potencies of these two cytokines. [less ▲]

Detailed reference viewed: 95 (3 UL)