Par1b/MARK2 is a Ser/Thr kinase with pleiotropic effects which participates in the generation of apico-basal polarity in C. elegans. It is phosphorylated by atypical PKC(ι/λ) in Thr595 and inhibited. Because previous work showed a decrease in aPKC activity under pro-inflammatory conditions, we analyzed the hypothesis that resulting decrease in Thr595-MARK2 with increased kinase activity may also participate in innate immunity. We confirmed that pT595-MARK2 was decreased under inflammatory stimulation. Increase in MARK2 activity was verified by Par3 delocalization and rescue with a specific inhibitor. MARK2 overexpression significantly enhanced the transcriptional activity of NF-kB for a subset of transcripts. It also resulted in phosphorylation of a single band (∼Mr 80,000) coimmunoprecipitating with RelA, identified as Med17. In vitro phosphorylation showed direct phosphorylation of Med17 in Ser152 by recombinant MARK2. Expression of S152D-Med17 mimicked the effect of MARK2 activation on downstream transcriptional regulation, which was antagonized by S152A-Med17. Decrease in pThr595 phosphorylation was validated in aPKC-deficient mouse jejunal mucosae. The transcriptional effects were confirmed in transcriptome analysis and transcript enrichment determinations in cells expressing S152D-Med17. We conclude that the axis MARK2- Med17 represents a novel form of crosstalk between polarity signaling and transcriptional regulation including, but not restricted to, innate immunity responses.

Par1b/MARK2 是一种具有多效性的 Ser/Thr 激酶，参与了秀丽隐杆线虫中顶端基底极性的产生. 它被 Thr595 中的非典型 PKC(ι/λ) 磷酸化并被抑制。因为先前的工作显示在促炎条件下 aPKC 活性降低，我们分析了导致 Thr595-MARK2 减少和激酶活性增加也可能参与先天免疫的假设。我们证实 pT595-MARK2 在炎症刺激下降低。MARK2 活性的增加通过 Par3 离域和使用特定抑制剂的救援来验证。MARK2 过表达显着增强了 NF-kB 对一部分转录本的转录活性。它还导致与 RelA 共免疫沉淀的单条带（~Mr 80,000）磷酸化，鉴定为 Med17。体外磷酸化显示重组 MARK2 直接磷酸化 Ser152 中的 Med17。S152D-Med17 的表达模拟了 MARK2 激活对下游转录调控的影响，后者被 S152A-Med17 拮抗。pThr595 磷酸化的降低在 aPKC 缺陷的小鼠空肠粘膜中得到验证。在表达 S152D-Med17 的细胞中的转录组分析和转录物富集测定中证实了转录效应。我们得出结论，轴 MARK2-Med17 代表了极性信号和转录调控之间的一种新形式的串扰，包括但不限于先天免疫反应。在表达 S152D-Med17 的细胞中的转录组分析和转录物富集测定中证实了转录效应。我们得出结论，轴 MARK2-Med17 代表了极性信号和转录调控之间的一种新形式的串扰，包括但不限于先天免疫反应。在表达 S152D-Med17 的细胞中的转录组分析和转录物富集测定中证实了转录效应。我们得出结论，轴 MARK2-Med17 代表了极性信号和转录调控之间的一种新形式的串扰，包括但不限于先天免疫反应。