Abstract
The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1alpha to IL-6 type cytokine signalling. SIRP1alpha binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1alpha protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1alpha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1alpha contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Cell Line
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Cytokine Receptor gp130 / metabolism
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Enzyme Induction / drug effects
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Extracellular Signal-Regulated MAP Kinases / biosynthesis
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Gene Expression Regulation / drug effects
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Humans
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Mice
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Models, Biological
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Phosphorylation / drug effects
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Phosphotyrosine / metabolism
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Proto-Oncogene Proteins c-fos / genetics
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction* / drug effects
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / metabolism
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Transcriptional Activation
Substances
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Interleukin-6
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Proto-Oncogene Proteins c-fos
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Ptpns1 protein, mouse
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Receptors, Immunologic
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Cytokine Receptor gp130
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Phosphotyrosine
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse