Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms.
The cytokine receptor subunits gp130, leukemia inhibitory factor receptor alpha (LIFRalpha), and oncostatin M receptor beta (OSMRbeta) 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 down-regulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFRalpha, and OSMRbeta 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 LIFRalpha degradation is promoted by activated ERK and that degradation of gp130, OSMRbeta, and a fraction of LIFRalpha 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.
Blanchard
F
F
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Wang
Y
Y
Kinzie
E
E
Duplomb
L
L
Godard
A
A
Baumann
H
H
D016475:3T3 Cells; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D053683:Oncostatin M / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology
C494200:Il6st protein, mouse; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; C508352:Osm protein, mouse; D011500:Protein Synthesis Inhibitors; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D003513:Cycloheximide