The STAT3-independent signaling pathway by glycoprotein 130 in hepatic cells.

Abstract

Interleukin (IL)-6 is a major regulator of hepatic acute-phase plasma protein (APP) genes. The membrane-proximal 133-amino acid cytoplasmic domain of glycoprotein (gp) 130, containing one copy of the Box3 motif, is sufficient to transmit a productive signal to endogenous APP genes in rat hepatoma H-35 cells. In contrast, a mutant gp130 domain lacking the Box3 motif activates Janus kinases to a normal level but fails to activate signal transducer and activator of transcription 3 and to up-regulate a number of APP genes, including thiostatin, fibrinogen, hemopexin, and haptoglobin. However, in the absence of Box3, gp130 still stimulates the expression of alpha2-macroglobulin and synergizes with IL-1 to up-regulate alpha1-acid glycoprotein. The Box3 motif is not required for activation of the SH2-containing protein tyrosine phosphatase 2 or the mitogen-activated protein kinase (MAPK), nor is the immediate induction of egr-1 and junB significantly altered. Surprisingly, gp130 without any functional Box3 stimulates prolonged activation of MAPK, leading to an extended period of up-regulation of egr-1 and to an extracellularly regulated kinase-mediated reduction in the IL-6-stimulated production of thiostatin. IL-6 reduces proliferation of H-35 cells through signaling by the Box3. In addition, cells expressing Box3-deficient gp130 showed distinct morphologic changes upon receptor activation. Taken together, these results indicate that Box3-derived and Box3-independent signals cooperate in the control of hepatic APP genes and that Box3 may be involved in the modulation of MAPK activity in gp130 signaling.

• Authors: C F Lai, J Ripperger, Y Wang, H Kim, R B Hawley, H Baumann
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 12 Pg. 7793-802 (Mar 19 1999) ISSN: 0021-9258 [Print] United States
• PMID: 10075671 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acute-Phase Proteins
• Antigens, CD
• DNA-Binding Proteins
• Il6st protein, rat
• Membrane Glycoproteins
• Recombinant Fusion Proteins
• STAT3 Transcription Factor
• Stat3 protein, rat
• Trans-Activators
• Cytokine Receptor gp130
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Acute-Phase Proteins (genetics, metabolism)
• Animals
• Antigens, CD (genetics, metabolism)
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Consensus Sequence
• Cytokine Receptor gp130
• DNA-Binding Proteins (metabolism)
• Liver (metabolism)
• Membrane Glycoproteins (genetics, metabolism)
• Mutagenesis, Site-Directed
• Rats
• Recombinant Fusion Proteins (metabolism)
• STAT3 Transcription Factor
• Signal Transduction
• Structure-Activity Relationship
• Trans-Activators (metabolism)
• Tumor Cells, Cultured