Stross Claudia, Radtke Simone, Clahsen Thomas, Gerlach Christa, Volkmer-Engert Rudolf, Schaper Fred, Heinrich Peter C, Hermanns Heike M
Institut für Biochemie, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
J Biol Chem. 2006 Mar 31;281(13):8458-68. doi: 10.1074/jbc.M511212200. Epub 2006 Feb 2.
Down-regulation of interleukin (IL)-6-type cytokine signaling has been shown to occur, among other mechanisms, via induction of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3). Binding of SOCS3 to the phosphorylated Tyr(759) in the cytoplasmic region of gp130, the common signal transducing receptor chain of all IL-6-type cytokines, is necessary for inhibition of Janus kinase-mediated signaling. In the present study, we analyzed the effect of SOCS3 on signal transduction by the proinflammatory cytokine oncostatin M (OSM), which signals through a receptor complex of gp130 and the OSM receptor (OSMR). OSM leads to a much stronger and prolonged induction of SOCS3 in HepG2 hepatoma cells and murine embryonal fibroblasts (MEF) compared with IL-6. A negative effect of SOCS3 on OSM signaling was confirmed using MEF cells lacking SOCS3. We can show that the OSMR-mediated signaling is inhibited by SOCS3 to a similar extent as previously described for gp130. However, the inhibition occurs independent of tyrosine motifs within the OSMR. Instead, SOCS3 interacts directly with JAK1 in a stimulation-dependent manner, a mechanism so far only known for SOCS1.
白细胞介素（IL）-6型细胞因子信号通路的下调已被证明可通过多种机制发生，其中包括诱导反馈抑制剂细胞因子信号转导抑制因子3（SOCS3）。SOCS3与gp130胞质区域中磷酸化的Tyr(759)结合，gp130是所有IL-6型细胞因子的共同信号转导受体链，这是抑制Janus激酶介导的信号传导所必需的。在本研究中，我们分析了SOCS3对促炎细胞因子抑瘤素M（OSM）信号转导的影响，OSM通过gp130和OSM受体（OSMR）的受体复合物发出信号。与IL-6相比，OSM在HepG2肝癌细胞和小鼠胚胎成纤维细胞（MEF）中导致更强且更持久的SOCS3诱导。使用缺乏SOCS3的MEF细胞证实了SOCS3对OSM信号传导的负面影响。我们可以证明，OSM受体介导的信号传导被SOCS3抑制的程度与先前描述的gp130相似。然而，这种抑制作用的发生与OSM受体中的酪氨酸基序无关。相反，SOCS3以刺激依赖的方式直接与JAK1相互作用，这是一种迄今为止仅为SOCS1所知的机制。
