EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. Meanwhile PP1, which functions as a phosphatase, is found to mediate MIIP-S303 dephosphorylation and its expression level inversely correlates with metastatic capability of tumor cells. Moreover, clinical analyses indicate the level of MIIP-S303 phosphorylation correlates with colorectal cancer (CRC) metastasis and prognosis. These findings uncover an unidentified mechanism underlying the precise regulation of NF-κB by EGF, and highlight the critical role of nuclear MIIP in tumor metastasis.In colorectal cancer, EGFR signalling is implicated in metastasis. Here, the authors unravel a mechanism through which EGF stimulation induces MIIP phosphorylation, leading to MIIP interacting with RelA-this prevents RelA deactylation and enhances transcriptional activity, facilitating metastasis.

中文翻译：

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PKCε通过抑制RelA脱乙酰基作用使MIIP磷酸化并促进结直肠癌转移。

EGFR信号传导与NF-κB激活有关。然而，在EGFR激活下调控NF-κB信号转导核心转导RelA / p65的具体机制还有待进一步阐明。在这里，我们表明EGF刺激诱导Ser303迁移和侵袭抑制蛋白（MIIP）的PKCε依赖性磷酸化；这种磷酸化促进了细胞核中MIIP与RelA之间的相互作用，从而MIIP阻止了组蛋白脱乙酰基酶6（HDAC6）介导的RelA脱乙酰化，从而增强了RelA的转录活性并促进了肿瘤转移。同时发现起磷酸酶作用的PP1介导MIIP-S303的去磷酸化，其表达水平与肿瘤细胞的转移能力成反比。而且，临床分析表明，MIIP-S303磷酸化水平与大肠癌（CRC）转移和预后相关。这些发现揭示了由EGF精确调节NF-κB的潜在机制，并突出了核MIIP在肿瘤转移中的关键作用。在结直肠癌中，EGFR信号传导与转移有关。在这里，作者揭示了一种机制，EGF刺激通过该机制诱导MIIP磷酸化，从而导致MIIP与RelA相互作用-这可防止RelA脱乙酰化并增强转录活性，从而促进转移。在结直肠癌中，EGFR信号传导与转移有关。在这里，作者揭示了一种机制，EGF刺激通过该机制诱导MIIP磷酸化，从而导致MIIP与RelA相互作用-这可防止RelA脱乙酰化并增强转录活性，从而促进转移。在结直肠癌中，EGFR信号传导与转移有关。在这里，作者揭示了一种机制，EGF刺激通过该机制诱导MIIP磷酸化，从而导致MIIP与RelA相互作用-这可防止RelA脱乙酰化并增强转录活性，从而促进转移。