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Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2000 Sep 01; Vol. 165 (5), pp. 2535-43. - Publication Year :
- 2000
-
Abstract
- Stimulation of the IL-6R complex leads to Src homology domain containing tyrosine phosphatase 2 (SHP2) recruitment to the receptor subunit gp130 and its subsequent tyrosine phosphorylation. SHP2 is a two-SH2 domain-containing protein tyrosine phosphatase that is activated by many cytokines and growth factors. SHP2 counteracts the activation of transcription factors of the STAT family and the induction of IL-6-responsive genes. Tyrosine 759 of gp130, the signal transducing subunit of the IL-6R complex, is essential for the phosphorylation of SHP2. Mutation of tyrosine 759 to phenylalanine leads to an enhanced inducibility of IL-6-dependent genes. Here we demonstrate that no further tyrosines in the cytoplasmic part of gp130 are required for the phosphorylation of SHP2. We also tested whether the tyrosine 759 motifs in both subunits of the gp130 dimer are required for SHP2 association and tyrosine phosphorylation. Interestingly, one SHP2-recruiting phosphotyrosine motif in a single chain of the gp130 dimer is sufficient to mediate SHP2 association to the gp130 receptor subunit and its tyrosine phosphorylation as well as to attenuate IL-6-dependent gene induction. Furthermore, we show that repression of gene induction via Y759 does not require the presence of the SHP2 and STAT recruitment sites within the same receptor subunit, but within the same receptor complex. The Y759 motif in gp130 also attenuates gene induction mediated by the oncostatin M and leukemia inhibitory factor receptor complexes, which both contain gp130 as the shared subunit.
- Subjects :
- Acute-Phase Proteins antagonists & inhibitors
Acute-Phase Proteins biosynthesis
Amino Acid Motifs
Animals
Antigens, CD chemistry
Antigens, CD physiology
Cytokine Receptor gp130
Dimerization
Enzyme Activation genetics
Enzyme Activation immunology
Gene Expression Regulation immunology
Growth Inhibitors genetics
Growth Inhibitors metabolism
Humans
Interleukin-6 genetics
Interleukin-6 metabolism
Intracellular Signaling Peptides and Proteins
Leukemia Inhibitory Factor
Leukemia Inhibitory Factor Receptor alpha Subunit
Lymphokines genetics
Lymphokines metabolism
Membrane Glycoproteins chemistry
Membrane Glycoproteins physiology
Mice
Mutagenesis, Site-Directed
Oncostatin M
Peptides genetics
Peptides metabolism
Phosphorylation
Protein Phosphatase 2
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases metabolism
Receptors, Cytokine antagonists & inhibitors
Receptors, Cytokine metabolism
Receptors, Cytokine physiology
Receptors, OSM-LIF
Receptors, Oncostatin M
SH2 Domain-Containing Protein Tyrosine Phosphatases
Signal Transduction genetics
Transcriptional Activation
Tyrosine chemistry
Tyrosine genetics
src Homology Domains immunology
Growth Inhibitors chemistry
Growth Inhibitors physiology
Interleukin-6 chemistry
Interleukin-6 physiology
Lymphokines chemistry
Lymphokines physiology
Peptides chemistry
Peptides physiology
Signal Transduction immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 165
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 10946280
- Full Text :
- https://doi.org/10.4049/jimmunol.165.5.2535