Oncostatin M signaling

Oncostatin M (OSM) is a member of the multifunctional cytokine interleukin 6 (IL6) - type cytokine family. It is mainly produced in activated T lymphocytes, macrophages, monocytes, neutrophils, and microglial cells. OSM signaling is initiated by the interaction of the cytokine to either: the type I LIFR-gp130 receptor complex, or to the type II OSMR-gp130 receptor [O’Hara et al]. The major downstream signaling pathways that are activated in OSM signaling are JAK/STAT, Ras/Raf/MAPK and PI3K pathways [Halfter, Halfter, Stross, Brantley]. As the receptors lack intrinsic tyrosine kinase activity, associated JAKs (JAK1, JAK2, JAK3 and TYK2) phosphorylate OSM receptor complex and STATs (STAT1, STAT3, STAT5A, STAT5B, STAT6) [O’Hara, Fritz, Migita, Hintzen]. Phosphorylated STATs form homodimeric complexes (STAT1, STAT3, STAT5B) or heterodimeric complex (STAT1-STAT3) and translocate to the nucleus. Once inside nucleus STAT proteins bind to regulatory elements in the promoter of OSM-responsive genes and regulate the gene expression [O’Hara, Halfter, Halfter, Hintzen]. Alternatively, OSM induced phosphorylation of PTPN11, GRB2, SHC1, Ras/Raf molecules can bring about the activation of ERK1/2 signaling module [O’Hara]. Oncostatin M -through ERK1/2 signaling module induces the phosphorylation of CEBPB, both CEBPB and EGR1 stimulates the transcription of genes involved in lipid metabolism [Zhang]. Although OSM also causes induced phosphorylation in MAPK family members (MAPK8/9/14) the functional importance of this is at present not well understood [O’Hara, Li]. OSM mediated signaling cascade is negatively regulated by JAK1 inhibition by SOCS3 and STAT3 inhibition by PIAS3 [Stross, Brantley, Chung]. OSM also induces the activation of caspase family members (CASP3, CASP7, CASP9) through the JAK2 module and regulates apoptosis [Auernhammer, Tiffen, Chipoy]. In osteosarcoma cells, OSM mediates apoptosis through a less understood STAT5B signaling module [Chipoy].

Oncostatin M（OSM）为多功能细胞因子白细胞介素6（IL6）型细胞因子家族的成员。其主要由活化T淋巴细胞、巨噬细胞、单核细胞、中性粒细胞和微胶质细胞产生。OSM信号传导的启动由细胞因子与以下任一受体的相互作用引发：I型LIFR-gp130受体复合物，或II型OSMR-gp130受体[O’Hara等人]。在OSM信号传导中激活的主要下游信号通路包括JAK/STAT、Ras/Raf/MAPK和PI3K通路[Halfter等人]。由于受体缺乏内在酪氨酸激酶活性，相关的JAKs（JAK1、JAK2、JAK3和TYK2）对OSM受体复合物和STATs（STAT1、STAT3、STAT5A、STAT5B、STAT6）进行磷酸化[O’Hara等人]。磷酸化的STATs形成同源二聚体复合物（STAT1、STAT3、STAT5B）或异源二聚体复合物（STAT1-STAT3），并转移至细胞核。一旦进入细胞核，STAT蛋白即与OSM响应基因启动子中的调控元件结合，并调节基因表达[O’Hara等人]。另一方面，OSM诱导的PTPN11、GRB2、SHC1、Ras/Raf分子磷酸化可激活ERK1/2信号模块[O’Hara]。通过ERK1/2信号模块，Oncostatin M诱导CEBPB的磷酸化，CEBPB和EGR1共同刺激参与脂质代谢的基因的转录[Zhang]。尽管OSM也会在MAPK家族成员（MAPK8/9/14）中引起诱导磷酸化，但此功能的重要性目前尚不明确[O’Hara、Li]。OSM介导的信号级联通过SOCS3抑制JAK1和PIAS3抑制STAT3进行负调节[Stross、Brantley、Chung]。OSM还通过JAK2模块诱导caspase家族成员（CASP3、CASP7、CASP9）的激活，并调节细胞凋亡[Auernhammer、Tiffen、Chipoy]。在骨肉瘤细胞中，OSM通过一个尚不明确的STAT5B信号模块介导细胞凋亡[Chipoy]。