References of "Graeve, L."
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See detailDifferential inhibition of IL-6-type cytokine-induced STAT activation by PMA
Terstegen, L.; Maassen, B. G.; Radtke, S. et al

in FEBS Letters (2000), 478(1-2), 100-4

Prior activation of mitogen-activated protein kinases by phorbol 13-myristate 12-acetate (PMA) results in an inhibition of interleukin (IL)-6-induced activation of the Janus kinase/signal transducer and ... [more ▼]

Prior activation of mitogen-activated protein kinases by phorbol 13-myristate 12-acetate (PMA) results in an inhibition of interleukin (IL)-6-induced activation of the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway which is most likely mediated by the induction of suppressor of cytokine signaling-3 and requires the specific SHP2 binding site Y759 of the IL-6 signal transducer gp130. In this study, we demonstrate that PMA inhibits STAT activation by IL-6 and the related cytokine leukemia inhibitory factor (LIF) but not by oncostatin M (OSM). Since the LIF receptor also contains an SHP2 recruitment site whereas the OSM receptor lacks such a module, we propose that two SHP2 binding modules within a homo- or heterodimeric receptor are necessary to mediate the PMA inhibitory effect. [less ▲]

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See detailTermination of IL-6-induced STAT activation is independent of receptor internalization but requires de novo protein synthesis
Thiel, S.; Sommer, U.; Kortylewski, M. et al

in FEBS Letters (2000), 470(1), 15-9

The interleukin-6 (IL-6) receptor complex comprises the IL-6 receptor (IL-6R, gp80) and the signal transducer gp130. Binding of IL-6 to its receptor results in dimerization of gp130, activation of the Jak ... [more ▼]

The interleukin-6 (IL-6) receptor complex comprises the IL-6 receptor (IL-6R, gp80) and the signal transducer gp130. Binding of IL-6 to its receptor results in dimerization of gp130, activation of the Jak/STAT pathway, and in a down-regulation of IL-6 binding sites by endocytosis. The STAT activation after stimulation is transient, being maximal after 15-30 min and disappearing after 60-90 min. The mechanism which leads to the termination of the signal is still unknown.In this paper we have studied whether the down-modulation of the STAT signal requires the endocytosis of the receptor complex. Our results suggest that the desensitization of the IL-6 signal is not due to internalization of the receptor complex but requires de novo protein synthesis. [less ▲]

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See detailIdentification of a Leu-lle internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor
Thiel, S.; Behrmann, Iris UL; Timmermann, A. et al

in Biochemical Journal (1999), 339 (Pt 1)

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor ... [more ▼]

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals. [less ▲]

Detailed reference viewed: 67 (0 UL)
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See detailInternalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway
Thiel, S.; Behrmann, Iris UL; Dittrich, E. et al

in Biochemical Journal (1998), 330 (Pt 1)

Signalling receptors often undergo receptor-mediated endocytosis. In many cases this internalization is stimulated by ligand binding and activation of intrinsic receptor tyrosine kinases, resulting in a ... [more ▼]

Signalling receptors often undergo receptor-mediated endocytosis. In many cases this internalization is stimulated by ligand binding and activation of intrinsic receptor tyrosine kinases, resulting in a receptor down-regulation. We have analysed whether internalization of the interleukin 6 signal transducer gp130 is dependent on the activation of receptor-associated Jak kinases. By using a chimaeric receptor system we found that receptor mutants that lack box1 and therefore are not capable of activating Jak and signal transducer and activator of transcription (STAT) proteins are still endocytosed efficiently. A chimaeric receptor with the recently identified dileucine internalization motif being replaced by two alanine residues was not efficiently internalized but still capable of recruiting STATs. Furthermore an antagonistic antibody that inhibits the signalling of all interleukin-6-type cytokines via gp130 was internalized as efficiently as an agonistic one that activates the Jak/STAT pathway. Our findings suggest that the endocytosis of gp130 is signal-independent. [less ▲]

Detailed reference viewed: 103 (0 UL)
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See detailInterleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
Heinrich, P. C.; Behrmann, Iris UL; Müller-Newen, G. et al

in Biochemical Journal (1998), 334 (Pt 2)

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1 ... [more ▼]

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals. [less ▲]

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See detailA single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation
Behrmann, Iris UL; Janzen, C.; Gerhartz, C. et al

in Journal of Biological Chemistry (1997), 272(8), 5269-74

We established a system of receptor chimeras that enabled us to induce heterodimerization of different cytoplasmic tails. Fusion constructs were created that are composed of the extracellular parts of the ... [more ▼]

We established a system of receptor chimeras that enabled us to induce heterodimerization of different cytoplasmic tails. Fusion constructs were created that are composed of the extracellular parts of the interleukin-5 receptor alpha and beta chains, respectively, and the transmembrane and intracellular parts of gp130, the signal transducing chain of the interleukin-6 receptor complex. In COS-7 transfectants we observed a dose-dependent interleukin-5-inducible STAT1 activation for which the presence of both the alpha and the beta chain chimera was needed. No STAT activity was detected if one of the cytoplasmic tails of the receptor complex was deleted, indicating that STAT activity resulted from a receptor dimer rather than from higher receptor aggregates. We further investigated whether dimerization of STAT1 depends on the juxtaposition of two STAT recruitment modules in a receptor complex. We show that a receptor dimer with only a single STAT1 docking site was still able to lead to STAT1 activation. This indicates that the formation of a paired set of STAT binding sites in a receptor complex is not the prerequisite for STAT factor dimerization. Our findings are discussed in view of alternative STAT dimerization models. [less ▲]

Detailed reference viewed: 107 (0 UL)