Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase

Abstract

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/lysosoreal 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.