Abstract
One of the major actions of interleukin-6 (IL-6) is the transcriptional activation of acute-phase plasma proteins (APP) genes in liver cells. Signaling by the IL-6 receptor is mediated through the signal transducing subunit gp130 and involves the activation of Janus-associated kinases (JAKs), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase. Functional analysis of gp130 in rat hepatoma cells by using transduced chimeric G-CSFR-gp130 receptor constructs demonstrates that SHP-2, the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase, acts as a negative regulator of the JAK/STAT signaling in part by downregulating JAK activity, thereby indirectly moderating the induction of STAT3-dependent APP genes. This study shows that in hepatoma cells, the recruitment and tyrosine phosphorylation of SHP-2, but not SHC, is the primary signaling event associated with the activation of MAP kinases (ERK1/2) by gp130. Overexpression of truncated SHP-2 that lacks Grb2-interacting sites, but not the full-length catalytically inactive SHP-2, reduces ERK activation by IL-6, confirming the signal-mediating role of SHP-2. Activation of ERK1/2 is correlated with induction of the immediate-early response genes. Stimulation of the c-fos, c-jun, and egr-1 genes is essentially absent in cells expressing gp130 with a Y759F mutation, which is unable to recruit SHP-2. Interestingly, both JAK/STAT and SHP-2 pathways regulate the induction of the junB gene. Moreover, disengagement of SHP-2 from gp130 signaling not only enhances APP gene induction but also further reduces cell proliferation, in part correlated with the attenuated expression of immediate-early response genes. These results suggest that IL-6 regulation of APP genes is affected by SHP-2 in two ways: SHP-2 acts as a phosphatase on the JAK/STAT pathway and serves as linker to the MAP kinase pathway, which in turn moderates APP production.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute-Phase Proteins / biosynthesis*
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Acute-Phase Proteins / genetics
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Acute-Phase Reaction / genetics*
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Adaptor Proteins, Signal Transducing*
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Animals
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Antigens, CD / physiology
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cytokine Receptor gp130
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DNA-Binding Proteins / physiology
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Enzyme Activation
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GRB2 Adaptor Protein
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Gene Expression Regulation*
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Gene Expression Regulation, Neoplastic
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Humans
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Interleukin-6 / physiology*
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 1
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Liver / drug effects
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Liver / metabolism*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms, Experimental / genetics
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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Membrane Glycoproteins / physiology
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / physiology*
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Protein-Tyrosine Kinases / physiology
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Proteins / metabolism
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Rats
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Receptors, Interleukin-6 / drug effects
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Receptors, Interleukin-6 / physiology*
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Recombinant Fusion Proteins / physiology
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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STAT3 Transcription Factor
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Signal Transduction / physiology*
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Trans-Activators / physiology
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Transcription, Genetic
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Transcriptional Activation
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Transfection
Substances
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Acute-Phase Proteins
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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DNA-Binding Proteins
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GRB2 Adaptor Protein
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GRB2 protein, human
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Grb2 protein, rat
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IL6ST protein, human
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Il6st protein, rat
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Neoplasm Proteins
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Proteins
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Receptors, Interleukin-6
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, rat
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Trans-Activators
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Cytokine Receptor gp130
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Jak1 protein, rat
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Janus Kinase 1
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, rat
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Ptpn6 protein, rat
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SH2 Domain-Containing Protein Tyrosine Phosphatases