Department of Pharmacy, UiT The Arctic University of Norway, 9037, Tromsø, Norway.
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany.
Sci Rep. 2020 Jul 9;10(1):11388. doi: 10.1038/s41598-020-68219-4.
Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth.
类固醇受体共激活因子-3（SRC-3）调节核激素受体和许多关键转录因子的活性。它参与细胞增殖、炎症的调节，并在包括乳腺癌、结直肠癌和肺癌在内的几种常见癌症的进展中发挥作用。磷酸化是控制 SRC-3 活性的一个重要调节事件。丝氨酸 857 是研究最多的磷酸化接受位点，其修饰已被报道对 SRC-3 依赖性肿瘤进展很重要。在这项研究中，我们表明，应激反应性 p38-MK2 信号通路在广泛的人类癌细胞中控制 SRC-3 在 S857 的磷酸化。p38-MK2 途径的激活导致 SRC-3 的核易位，从而有助于 NF-kB 的反式激活，从而调节 IL-6 转录。将 p38-MK2 信号轴鉴定为 SRC-3 磷酸化和活性的关键调节剂，为开发和测试新的治疗策略以控制增殖和转移性肿瘤生长开辟了新的可能性。
