Laszlo George S, Nathanson Neil M
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
J Biol Chem. 2003 Jul 25;278(30):27750-7. doi: 10.1074/jbc.M303670200. Epub 2003 May 21.
Members of the interleukin-6 (IL-6) family of cytokines exert their biological effects via binding to their cognate ligand-binding receptor subunit on a target cell. The subsequent recruitment of the common signal transducer glycoprotein 130 and activation of the JAK/STAT and SHP-2/Ras/mitogen-activated protein kinase (MAPK) pathways are responsible for the majority of cellular responses elicited by IL-6 cytokines. Several types of experiments suggest that the Src family of kinases (SFK) also participates in IL-6 family cytokine-mediated signaling events. SYF cells, which lack expression of SFKs Src, Yes, and Fyn, were used to determine the role of SFKs in IL-6 family cytokine signaling and gene induction. SYF and wild type (WT) control fibroblasts displayed similar activation of signaling intermediates following stimulation with leukemia inhibitory factor (LIF). LIF-stimulated tyrosine phosphorylation of SHP-2 and subsequent activation of MAPK in SYF cells were identical to that seen in LIF-stimulated WT cells. Both LIF-stimulated tyrosine phosphorylation of STAT1 and STAT3, as well as LIF-stimulated DNA binding activity of STAT-containing nuclear complexes were indistinguishable when compared in SYF and WT cells. In addition, the phosphatidylinositol 3-kinase-sensitive Akt kinase and p38 MAPK were activated by LIF in both SYF and WT cells. Furthermore, LIF-stimulated expression of c-fos, egr-1, and suppressor of cytokine signaling-3 was retained in SYF cells. The IL-6 family cytokine oncostatin M was also capable of activating MAPK, STAT3, STAT1, Akt, and p38 in both WT and SYF cells. These results demonstrate that IL-6 family cytokines can activate a full repertoire of signaling pathways and induce gene expression independent of SFKs.
白细胞介素-6（IL-6）细胞因子家族的成员通过与靶细胞上其同源配体结合受体亚基结合来发挥其生物学效应。随后募集共同信号转导子糖蛋白130以及激活JAK/STAT和SHP-2/Ras/丝裂原活化蛋白激酶（MAPK）途径，这是IL-6细胞因子引发的大多数细胞反应的原因。几种类型的实验表明，Src激酶家族（SFK）也参与IL-6家族细胞因子介导的信号转导事件。缺乏SFKs Src、Yes和Fyn表达的SYF细胞被用于确定SFKs在IL-6家族细胞因子信号转导和基因诱导中的作用。在用白血病抑制因子（LIF）刺激后，SYF和野生型（WT）对照成纤维细胞显示出相似的信号中间体激活。LIF刺激SYF细胞中SHP-2的酪氨酸磷酸化以及随后的MAPK激活与LIF刺激的WT细胞中所见相同。在SYF和WT细胞中比较时，LIF刺激的STAT1和STAT3的酪氨酸磷酸化以及LIF刺激的含STAT核复合物的DNA结合活性没有区别。此外，磷脂酰肌醇3激酶敏感的Akt激酶和p38 MAPK在SYF和WT细胞中均被LIF激活。此外，LIF刺激的c-fos、egr-1和细胞因子信号转导抑制因子3的表达在SYF细胞中得以保留。IL-6家族细胞因子制瘤素M在WT和SYF细胞中也能够激活MAPK、STAT3、STAT1、Akt和p38。这些结果表明，IL-6家族细胞因子可以激活完整的信号转导途径并诱导基因表达，而与SFKs无关。
