Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

• Published in: The Journal of biological chemistry Vol. 275; no. 37; pp. 28793 - 28801
• Main Authors: Blanchard, F, Duplomb, L, Wang, Y, Robledo, O, Kinzie, E, Pitard, V, Godard, A, Jacques, Y, Baumann, H
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 15.09.2000
• Subjects: 3T3 Cells; Amino Acid Motifs; Animals; Down-Regulation; Endocytosis; Enzyme Activation; glycoprotein gp130; Growth Inhibitors - pharmacology; HeLa Cells; Humans; interleukin 6 receptors; Interleukin-6; Leukemia Inhibitory Factor; Leukemia Inhibitory Factor Receptor alpha Subunit; leukemia inhibitory factor receptors; Liver Neoplasms - metabolism; Lymphokines - pharmacology; Lysosomes - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - physiology; oncostatin M; Rats; Receptors, Cytokine - metabolism; Receptors, OSM-LIF
• DOI: 10.1074/jbc.M003986200
• ISSN: 0021-9258

Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor α subunit (LIFRα) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFRα decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFRα down-regulation. The regulated loss of LIFRα is specific since neither gp130 nor OSM receptor β shows a comparable change in turnover. LIFRα down-regulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFRα, we demonstrate that LIFRα down-regulation depends on activation of extracellular signal-regulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFRα at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFRα. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFRα half-life.