Modulation of the interleukin-6 receptor subunit glycoprotein 130 complex and its signaling by LMO4 interaction.
The interleukin (IL)-6-type cytokines play major roles in a variety of biological processes by signaling through a common receptor subunit, glycoprotein (gp) 130. We performed yeast two-hybrid screening to identify new binding partners of the activated gp130 and the associated Janus kinases. LMO4, a LIM domain-containing protein that belongs to ... a family of oncogenes, was identified in this assay. Further studies show that LMO4 associates with gp130 and Janus kinase1 in several mammalian cell types. It also interacts with protein-tyrosine phosphatase 2 (SHP2) and suppressor of cytokine signaling 3 (SOCS3). The binding domains involved in these interactions were mapped, and the interactions were shown to be in a direct manner by in vitro binding assays. It is likely that LMO4 exists in the gp130 complex. The cellular localization of LMO4 was detected primarily in the nucleus with a substantial amount also detected in the cytoplasm in several cell types. The effect of LMO4 in IL-6 signaling was subsequently examined. Overexpression of LMO4 enhanced the transcriptional activity and target gene expression of Stat 3 (signal transducers and activators of transcription 3). Consistent with this, silencing LMO4 expression in stable cell lines expressing the small interfering RNA of LMO4 decreased Stat3 activity. Furthermore, the half-life of gp130 was shortened, and the production of acute phase proteins induced by IL-6 was reduced. Together, our data reveal a positive regulatory role of LMO4 in IL-6 signaling, possibly by acting as a scaffold for stabilization of the gp130 complex. These studies may open up a link between the oncogenic effect of LMO proteins and their regulatory role in cytokine signaling in general.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Antigens, CD, Blotting, Northern, COS Cells, Cell Line, Cell Line, Tumor, Cell Nucleus, Cytokine Receptor gp130, Cytokines, Cytoplasm, DNA-Binding Proteins, Down-Regulation, Gene Silencing, Genes, Reporter, Glutathione Transferase, Homeodomain Proteins, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Membrane Glycoproteins, Microscopy, Fluorescence, Phosphorylation, Plasmids, Protein Binding, Protein Phosphatase 2, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, RNA, Small Interfering, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transfection, Two-Hybrid System Techniques, Tyrosine
Adaptor Proteins, Signal Transducing, Animals, Antigens, CD, Blotting, Northern, COS Cells, Cell Line, Cell Line, Tumor, Cell Nucleus, Cytokine Receptor gp130, Cytokines, Cytoplasm, DNA-Binding Proteins, Down-Regulation, Gene Silencing, Genes, Reporter, Glutathione Transferase, Homeodomain Proteins, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Membrane Glycoproteins, Microscopy, Fluorescence, Phosphorylation, Plasmids, Protein Binding, Protein Phosphatase 2, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, RNA, Small Interfering, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transfection, Two-Hybrid System Techniques, Tyrosine
J. Biol. Chem.
Date: Apr. 01, 2005
PubMed ID: 15677447
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