Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China.
Department of Respiratory Diseases, Changhai Hospital, the Second Military Medical University, Shanghai, China.
FEBS Open Bio. 2022 Oct;12(10):1747-1760. doi: 10.1002/2211-5463.13458. Epub 2022 Aug 17.
Tumor necrosis factor receptor-associated factor 4 (TRAF4) is overexpressed in a variety of carcinomas of different origins, but its role in tumorigenesis remains incompletely understood. Previous studies suggest that TRAF4 promotes epidermal growth factor receptor (EGFR) activation in non-small cell lung cancer (NSCLC). However, the downstream signaling pathway of TRAF4-mediated EGFR activation, as well as its effects on tumor cells, have not been fully elucidated. Here we report that TRAF4 overexpression is associated with increased activity of extracellular signal-regulated kinase 5 (ERK5) in NSCLC tissues. Activation of ERK5 was dependent on TRAF4-mediated EGFR activation, since inhibition of either TRAF4 or EGFR dramatically abolished phosphorylation of ERK5. Mechanistically, EGFR recruited mitogen-activated protein kinase kinase kinase 3 (MEKK3), an upstream kinase of ERK5, in a TRAF4-dependent manner. Thus, our data suggest that an EGFR-TRAF4-MEKK3-ERK5 axis promotes the proliferation of tumor cells, and this may be a potential target for therapeutic intervention of NSCLC.
肿瘤坏死因子受体相关因子 4（TRAF4）在多种不同来源的癌中过表达，但它在肿瘤发生中的作用仍不完全清楚。先前的研究表明，TRAF4 促进非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）的激活。然而，TRAF4 介导的 EGFR 激活的下游信号通路及其对肿瘤细胞的影响尚未完全阐明。在这里，我们报告 TRAF4 的过表达与 NSCLC 组织中细胞外信号调节激酶 5（ERK5）活性的增加有关。ERK5 的激活依赖于 TRAF4 介导的 EGFR 激活，因为 TRAF4 或 EGFR 的抑制都显著消除了 ERK5 的磷酸化。在机制上，EGFR 以 TRAF4 依赖性的方式募集细胞外信号调节激酶 5（ERK5）的上游激酶丝裂原活化蛋白激酶激酶激酶 3（MEKK3）。因此，我们的数据表明，EGFR-TRAF4-MEKK3-ERK5 轴促进肿瘤细胞的增殖，这可能是 NSCLC 治疗干预的一个潜在靶点。
