Signaling of MK2 sustains robust AP1 activity for triple negative breast cancer tumorigenesis through direct phosphorylation of JAB1.
Signaling of MK2 sustains robust AP1 activity for triple negative breast cancer tumorigenesis through direct phosphorylation of JAB1.
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DOI：
10.1038/s41523-021-00300-1
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发表时间：
2021-07-09
影响因子：
5.9
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Chen H;Padia R;Li T;Li Y;Li B;Jin L;Huang S
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 （activator protein 1, AP1）转录因子在侵袭中的重要性一致，AP1在TNBC细胞系中的活性远高于ER +细胞系。在TNBC细胞中，ERK和p38MAPK信号通路促进了AP1的活性。ERK信号通路通过控制AP1转录因子的丰度来调节AP1活性，而p38MAPK信号通路通过增强AP1与AP1位点的结合而不改变其丰度来调节AP1活性。在这里，我们发现p38MAPK对AP1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，而且在TNBC细胞中直接磷酸化JAB1的Ser177位点。有趣的是，Ser177磷酸化不影响JAB1和JUN的相互作用。相反，干扰p38MAPK信号通路或在JAB1的Ser177上引入S到A点突变，可以减少JUN在周期蛋白D1、尿激酶纤解酶原激活物（uPA）和uPA受体启动子中AP1位点的募集。此外，在TNBC细胞中，JAB1的敲除降低了约60%的AP1转录活性。综上所述，这些结果表明mk2介导的JAB1磷酸化促进JUN招募到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可显著降低TNBC细胞生长、体外侵袭和体内肿瘤生长。该研究表明p38MAPK-MK2信号通路通过维持AP1活性促进TNBC肿瘤发生。
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 p38MAPK signaling pathways. While ERK signaling pathway regulates AP1 activity by controlling the abundance of AP1 transcription factors, p38MAPK signaling pathway does it by enhancing AP1 binding to AP1 sites without altering their abundance. Here, we show that p38MAPK 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 p38MAPK 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 p38MAPK-MK2 signaling pathway promotes TNBC tumorigenesis by sustaining robust AP1 activity.
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影响因子：
7.3
作者：
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DOI：
10.1073/pnas.90.8.3299
发表时间：
1993-04-15
影响因子：
11.1
作者：
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通讯作者：
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