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2. TNF-alpha induces tyrosine phosphorylation and recruitment of the Src homology protein-tyrosine phosphatase 2 to the gp130 signal-transducing subunit of the IL-6 receptor complex.

Author

Bode JG, Schweigart J, Kehrmann J, Ehlting C, Schaper F, Heinrich PC, and Häussinger D

Subjects
3T3 Cells, Amino Acid Substitution genetics, Animals, Antigens, CD genetics, Antigens, CD physiology, Cell Line, Cytokine Receptor gp130, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Enzyme Activation genetics, Enzyme Activation immunology, Interleukin-6 antagonists & inhibitors, Interleukin-6 physiology, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins genetics, Membrane Glycoproteins physiology, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases metabolism, Mitogen-Activated Protein Kinases physiology, Phenylalanine genetics, Phosphorylation, Protein Phosphatase 2, Protein Subunits genetics, Protein Subunits physiology, Protein Transport genetics, Protein Transport immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases antagonists & inhibitors, Protein Tyrosine Phosphatases genetics, Protein Tyrosine Phosphatases physiology, Protein-Tyrosine Kinases metabolism, Protein-Tyrosine Kinases physiology, Receptors, Interleukin-6 physiology, SH2 Domain-Containing Protein Tyrosine Phosphatases, STAT3 Transcription Factor, Signal Transduction genetics, Trans-Activators antagonists & inhibitors, Trans-Activators metabolism, Transfection, Tyrosine genetics, Tyrosine physiology, p38 Mitogen-Activated Protein Kinases, src Homology Domains genetics, Antigens, CD metabolism, Membrane Glycoproteins metabolism, Protein Subunits metabolism, Protein Tyrosine Phosphatases metabolism, Receptors, Interleukin-6 metabolism, Signal Transduction immunology, Tumor Necrosis Factor-alpha physiology, Tyrosine metabolism, src Homology Domains immunology
Abstract

Recently, it has been demonstrated that TNF-alpha and LPS induce the expression of suppressor of cytokine signaling 3 (SOCS3) and inhibit IL-6-induced STAT3 activation in macrophages. Inhibitor studies suggested that both induction of SOCS3 and inhibition of IL-6-induced STAT3 activation depend on the activation of p38 mitogen-activated protein kinase. Since recruitment of the tyrosine phosphatase Src homology protein tyrosine phosphatase 2 (SHP2) to the signal-transducing receptor subunit gp130 attenuates IL-6-mediated STAT-activation, we were interested in whether TNF-alpha also induces the association of SHP2 to the gp130 receptor subunit. In this study we demonstrate that stimulation of macrophages and fibroblast cell lines with TNF-alpha causes the recruitment of SHP2 to the gp130 signal-transducing subunit and leads to tyrosine phosphorylation of SHP2 and gp130. In this context the cytoplasmic SHP2/SOCS3 recruitment site of gp130 tyrosine 759 is shown to be important for the inhibitory effects of TNF-alpha, since mutation of this residue completely restores IL-6-stimulated activation of STAT3 and, consequently, of a STAT3-dependent promoter. In this respect murine fibroblasts lacking exon 3 of SHP2 are not sensitive to TNF-alpha, indicating that functional SHP2 and its recruitment to gp130 are key events in inhibition of IL-6-dependent STAT activation by TNF-alpha. Furthermore, activation of p38 mitogen-activated protein kinase is shown to be essential for the inhibitory effect of TNF-alpha on IL-6 signaling and TNF-alpha-dependent recruitment of SHP2 to gp130.

Published
2003
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