Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation.
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.
Anhuf
D
D
Department of Biochemistry, Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany.
Weissenbach
M
M
Schmitz
J
J
Sobota
R
R
Hermanns
H M
HM
Radtke
S
S
Linnemann
S
S
Behrmann
I
I
Heinrich
P C
PC
Schaper
F
F
D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology; D050822:Cytokine Receptor gp130; D019281:Dimerization; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D053683:Oncostatin M; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics; D018909:src Homology Domains / Q000276:immunology
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D054648:Protein Phosphatase 2; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases