Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 50, Pages 47038-47045Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M107971200
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Funding
- NCI NIH HHS [CA 16056, CA 85580] Funding Source: Medline
- NIDDK NIH HHS [DK 38866] Funding Source: Medline
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The cytokine receptor subunits gp130, leukemia inhibitory factor receptor alpha (LIFR alpha), and oncostatin M receptor beta (OSMR beta) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by downregulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFR alpha, and OSMR beta by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFRa degradation is promoted by activated ERK and that degradation of gp130, OSMR beta, and a fraction of LIFR alpha involves mechanisms that are separate from signal transduction. These mechanisms include ligand-mediated dimerization, internalization, and endosomal/lysosomal degradation. Proteosomal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding.
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