Reference : SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130
Lehmann, U. [> >]
Schmitz, J. [> >]
Weissenbach, M. [> >]
Sobota, R. M. [> >]
Hortner, M. [> >]
Friederichs, K. [> >]
Behrmann, Iris mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Tsiaris, W. [> >]
Sasaki, A. [> >]
Schneider-Mergener, J. [> >]
Yoshimura, A. [> >]
Neel, B. G. [> >]
Heinrich, P. C. [> >]
Schaper, F. [> >]
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Yes (verified by ORBilu)
[en] src Homology Domains ; Macromolecular Substances ; Janus Kinase 1 ; Intracellular Signaling Peptides and Proteins ; Interleukin-6 ; Humans ; Genes, Reporter ; Fibroblasts ; Enzyme Activation ; Cytokine Receptor gp130 ; Cell Nucleus ; Cell Line ; Biosensing Techniques ; Antigens, CD ; Animals ; Membrane Glycoproteins ; Mice ; Mitogen-Activated Protein Kinases ; Tyrosine ; Transcription Factors ; Suppressor of Cytokine Signaling Proteins ; Signal Transduction ; SH2 Domain-Containing Protein Tyrosine Phosphatases ; Repressor Proteins ; Recombinant Fusion Proteins ; Receptors, Erythropoietin ; Proteins ; Protein-Tyrosine Kinases ; Protein Tyrosine Phosphatases ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Binding ; Molecular Sequence Data ; Amino Acid Sequence
[en] Interleukin-6 (IL-6) activates the Jak/STAT pathway as well as the mitogen-activated protein kinase cascade. Tyrosine 759 of the IL-6 signal-transducing receptor subunit gp130 has been identified as being involved in negative regulation of IL-6-induced gene induction and activation of the Jak/STAT pathway. Because this site is known to be a recruitment motif for the protein-tyrosine phosphatase SHP2, it has been suggested that SHP2 is the mediator of tyrosine 759-dependent signal attenuation. We recently observed that the suppressor of cytokine-signaling SOCS3 also acts through the tyrosine motif 759 of gp130. However, the relative contributions of SHP2 and SOCS3 to the repression of IL-6 signaling are not understood. Therefore, we designed experiments allowing the independent recruitment of each of these proteins to the IL-6-receptor complex. We show that receptor- and membrane-targeted SHP2 counteracts IL-6 signaling independent of SOCS3 binding to gp130. On the other hand, SOCS3 inhibits signaling in cells expressing a truncated SHP2 protein, which is not recruited to gp130. These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130.

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