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

Anastasia Mashukova, Radia Forteza, Viraj N. Shah, Pedro J. Salas

Research output: Contribution to journalArticlepeer-review

Abstract

Par1b/MARK2 is a Ser/Thr kinase with pleiotropic effects that participates in the generation of apico-basal polarity in Caenorhabditis elegans. It is phosphorylated by atypical PKC(ι/λ) in Thr595 and inhibited. Because previous work showed a decrease in atypical protein kinase C (aPKC) activity under proinflammatory conditions, we analyzed the hypothesis that the 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. The 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. The 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 theMARK2-Med17 axis represents a novel form of crosstalk between polarity signaling and transcriptional regulation including, but not restricted to, innate immunity responses.

Original languageEnglish (US)
Pages (from-to)690-702
Number of pages13
JournalMolecular biology of the cell
Volume32
Issue number8
DOIs
StatePublished - Apr 15 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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