Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611-0700, USA.
Biochem J. 2012 Apr 15;443(2):329-38. doi: 10.1042/BJ20112187.
Many cytokines, hormones and growth factors use the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway for cell signalling and specific gene activation. In the classical model, ligand is said to interact solely with the receptor extracellular domain, which triggers JAK activation of STATs at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific gene activation. Given the limited number of STATs (seven) and the activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on IFNγ (interferon γ), we have shown that ligand, receptor and activated JAKs are involved in nuclear events that are associated with specific gene activation, where the receptor subunit IFNGR1 (IFNγ receptor 1) functions as a transcription/co-transcription factor and the JAKs are involved in key epigenetic events. RTKs (receptor tyrosine kinases) such as EGFR [EGF (epidermal growth factor) receptor] and FGFR [FGF (fibroblast growth factor) receptor] also undergo nuclear translocation in association with their respective ligands. EGFR and FGFR, like IFNGR1, have been shown to function as transcription/co-transcription factors. The RTKs also regulate other kinases that have epigenetic effects. Our IFNγ model, as well as the RTKs EGFR and FGFR, have similarities to that of steroid receptor signalling. These systems consist of ligand-receptor-co-activator complexes at the genes that they activate. The co-activators consist of transcription factors and kinases, of which the latter play an important role in the associated epigenetics. It is our view that signalling by cytokines such as IFNγ is but a variation of specific gene activation by steroid hormones.
许多细胞因子、激素和生长因子利用 JAK（Janus kinase）/STAT（信号转导和转录激活因子）途径进行细胞信号传递和特定基因激活。在经典模型中，配体被认为仅与受体细胞外结构域相互作用，该结构域触发受体细胞质结构域中 JAK 的 STAT 激活。然后，激活的 STAT 被认为执行特定基因激活的核事件。鉴于 STAT 的数量有限（七种），以及具有不同功能的细胞因子激活相同的 STAT，其信号转导特异性的机制并不明显。我们专注于 IFNγ（干扰素 γ），已经表明配体、受体和激活的 JAK 参与与特定基因激活相关的核事件，其中受体亚基 IFNGR1（IFNγ 受体 1）作为转录/共转录因子发挥作用，而 JAK 则参与关键的表观遗传事件。RTKs（受体酪氨酸激酶），如 EGFR[EGF（表皮生长因子）受体]和 FGFR[FGF（成纤维细胞生长因子）受体]，也与各自的配体一起发生核易位。EGFR 和 FGFR 与 IFNGR1 一样，已被证明作为转录/共转录因子发挥作用。RTKs 还调节具有表观遗传效应的其他激酶。我们的 IFNγ 模型以及 RTKs EGFR 和 FGFR，与类固醇受体信号转导相似。这些系统在它们激活的基因中包含配体-受体-共激活剂复合物。共激活剂由转录因子和激酶组成，其中后者在相关的表观遗传学中起着重要作用。我们认为，IFNγ 等细胞因子的信号传递只是类固醇激素特定基因激活的一种变体。
