Triple negative breast cancer (TNBC) cells are generally more invasive than estrogen receptor-positive (ER + ) breast cancer cells. Consistent with the importance of activator protein 1 (AP1) transcription factors in invasion, AP1 activity is much higher in TNBC lines than ER + lines. In TNBC cells, robust AP1 activity is facilitated by both ERK and p38^MAPK signaling pathways. While ERK signaling pathway regulates AP1 activity by controlling the abundance of AP1 transcription factors, p38^MAPK signaling pathway does it by enhancing AP1 binding to AP1 sites without altering their abundance. Here, we show that p38^MAPK regulation of AP1 activity involves both MAPKAPK2 (MK2) and JAB1, a known JUN-binding protein. MK2 not only interacts with JAB1 but also directly phosphorylates JAB1 at Ser177 in TNBC cells. Interestingly, Ser177 phosphorylation does not affect JAB1 and JUN interaction. Instead, interfering with p38^MAPK signaling pathway or introducing an S to A point mutation at Ser177 of JAB1 reduces JUN recruitment to the AP1 sites in cyclin D1, urokinase plasminogen activator (uPA) and uPA receptor promoters. Moreover, knockdown of JAB1 diminishes >60% of AP1 transcriptional activity in TNBC cells. Taken together, these results indicate that MK2-mediated phosphorylation of JAB1 facilitates JUN recruitment to AP1 sites, thus augmenting AP1 activity. In line with the role of JAB1 in AP1 activity, silencing JAB1 leads to dramatic reduction in TNBC cell growth, in vitro invasion and in vivo tumor outgrowth. This study suggests that the p38^MAPK-MK2 signaling pathway promotes TNBC tumorigenesis by sustaining robust AP1 activity.

三阴性乳腺癌 (TNBC) 细胞通常比雌激素受体阳性 (ER + ) 乳腺癌细胞更具侵袭性。与激活蛋白 1 (AP1) 转录因子在侵袭中的重要性一致，AP1 活性在 TNBC 细胞系中远高于 ER + 细胞系。^{在 TNBC 细胞中，ERK 和 p38 MAPK}信号通路促进了强大的 AP1 活性。ERK 信号通路通过控制 AP1 转录因子的丰度来调节 AP1 活性，而 p38 ^MAPK信号通路通过增强 AP1 与 AP1 位点的结合而不改变它们的丰度来实现。在这里，我们展示了 p38 ^MAPKAP1 活性的调节涉及 MAPKAPK2 (MK2) 和 JAB1，一种已知的 JUN 结合蛋白。MK2 不仅与 JAB1 相互作用，而且直接磷酸化 TNBC 细胞中 Ser177 位点的 JAB1。有趣的是，Ser177 磷酸化不影响 JAB1 和 JUN 的相互作用。相反，干扰 p38 ^MAPK信号通路或在 JAB1 的 Ser177 引入 S 至 A 点突变可减少细胞周期蛋白 D1、尿激酶纤溶酶原激活物 (uPA) 和 uPA 受体启动子中 AP1 位点的 JUN 募集。此外，JAB1 的敲低降低了 TNBC 细胞中 >60% 的 AP1 转录活性。总之，这些结果表明 MK2 介导的 JAB1 磷酸化促进 JUN 募集到 AP1 位点，从而增强 AP1 活性。与 JAB1 在 AP1 活性中的作用一致，沉默 JAB1 会导致 TNBC 细胞生长、体外侵袭和体内肿瘤生长显着减少。这项研究表明，p38 ^MAPK -MK2 信号通路通过维持强大的 AP1 活性来促进 TNBC 肿瘤发生。