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

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