Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase
Stimulation of leukemia inhibitory factor receptor degradation by extracellular signal-regulated kinase
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DOI：
10.1074/jbc.m003986200
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发表时间：
2000-09-15
影响因子：
4.8
通讯作者：
Baumann, H
中科院分区：
文献类型：
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作者：
Blanchard, F;Duplomb, L;Baumann, H
白血病抑制因子(LIF)通过异二聚体受体复合体传递信号，该复合体包括LIF受体α亚基(LIFRα)和白细胞介素6细胞因子受体的共同信号转导亚单位gp130。这项研究表明，在不同类型的细胞中，在LIF或密切相关的细胞因子抑癌素M(OSM)处理过程中，LIFRα水平下降。此外，胰岛素和表皮生长因子可诱导类似的LIFRα下调。由于gp130和OSM受体β都没有显示出类似的周转变化，所以LIFRα的调节丢失是特异的。LIFRα下调与细胞对LIF的反应性降低相关。利用蛋白激酶抑制剂和LIFRα的点突变，我们证明LIFRα的下调依赖于细胞外信号调节激酶1/2的激活和LIFRα胞浆结构域在丝氨酸185的磷酸化。这一修改。似乎促进了LIFRα的内体/溶酶体途径。这些结果表明，细胞外信号调节的激酶激活因子，如OSM和生长因子，有可能通过调节LIFRα半衰期来降低体内LIF的反应性。
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.