SETβ是乳腺癌各种细胞系中致癌蛋白SE转位(SET)主要的亚型。相互作用组-转录组分析表明，SETβ与细胞应激反应密切相关。在各种外源性刺激中，甲醛(FA)以剂量依赖方式引起明显的生物学效应。在不同浓度下，SET动态穿梭于细胞核和细胞质之间，执行多种生物功能以恢复稳态。在低浓度下，FA作为表皮生长因子(EGF)作用，激活HER2受体和HER2+乳腺癌细胞下游信号通路，导致细胞增殖增强。SETβ的核质转运受PI3K/PKCα/CK2α轴控制，SETβ核质转运受阻抑制EGF诱导的AKT和ERK激活。SETβ不仅抑制了应激诱导的p38 MAPK信号通路的激活，还通过阻碍G3BP1-RNA复合物的形成，妨碍了应激颗粒的组装。我们的发现表明，SET是一个重要的调节器，可以动态调节细胞应激信号通路。© 2022. The Author(s), under exclusive licence to Springer Nature B.V.

SETβ is the predominant isoform of oncoprotein SE translocation (SET) in various breast cancer cell lines. Interactome-transcriptome analysis has shown that SETβ is intimately associated with cellular stress response. Among various exogenous stimuli, formaldehyde (FA) causes distinct biological effects in a dose-dependent manner. In response to FA at different concentrations, SET dynamically shuttles between the nucleus and cytoplasm, performing diverse biofunctions to restore homeostasis. At a low concentration, FA acts as an epidermal growth factor (EGF) and activates the HER2 receptor and downstream signaling pathways in HER2+ breast cancer cells, resulting in enhanced cell proliferation. Nucleocytoplasmic transport of SETβ is controlled by the PI3K/PKCα/CK2α axis and depletion or blockade of the transport of SETβ suppresses EGF-induced activation of AKT and ERK. SETβ also inhibits not only stress-induced activation of p38 MAPK signaling pathway, but also assembly of stress granules by hindering formation of the G3BP1-RNA complex. Our findings suggest that SET functions as an important regulator which modulates cellular stress signaling pathways dynamically.© 2022. The Author(s), under exclusive licence to Springer Nature B.V.