The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80

Abstract

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.

NF-κB signaling in neoplastic transition from epithelial to mesenchymal phenotype

“…MARK2 then phosphorylates Par3, releasing it from the polarity complex, which results in changes in Par3 cytoplasmic distribution and changes in cellular polarity. It was shown that stimulation of NF-κB/IFN by TNFα and IFNγ leads to the downregulation of aPKC in intestinal epithelial cells resulting in an increase in NF-κB activity and chronic inflammation linked to elevated expression of IL-8 and CXCL1 [ 58 ]. All these observations suggest that NF-κB is linked to EMT-induced downregulation of polarity genes, driving the loss of apical-basolateral polarity.…”