Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs

Simon Rousseau, Nick Morrice, Mark Peggie, David G. Campbell, Matthias Gaestel, Philip Cohen

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    187 Citations (Scopus)


    Lipopolysaccharide (LPS) stimulates production of inflammatory mediators, partly by stabilizing [interleukin-6 (IL-6), cyclooxygenase 2 (COX-2)] and/or stimulating translation [tumour necrosis factor- (TNF-)] of their mRNAs. Such regulation depends on AU-rich elements (AREs) within the 3'-untranslated regions and is partially suppressed by SB 203580 (which inhibits SAPK2a/p38). The LPS-induced production of TNF- and IL-6 is suppressed in MAPKAP-K2-deficient mice (a kinase activated by SAPK2a/p38). Here, we identify 18 macrophage proteins that bind to AREs and show that hnRNP A0 is a major substrate for MAPKAP-K2 in this fraction. MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. Phosphorylation was prevented by SB 203580 and suppressed in macrophages derived from MAPKAP-K2-deficient mice. The mRNAs encoding TNF-, COX-2 and macrophage inflammatory protein-2 (MIP-2) bound to hnRNP A0 in LPS-stimulated macrophages, an interaction prevented by SB 203580. The LPS-induced stabilization of MIP-2 mRNA and production of MIP-2 protein were abolished when macrophages were incubated with SB 203580 plus PD 184352 (which inhibits the classical MAP kinase cascade). Our data suggest that LPS-induced binding of hnRNP A0 to AREs may contribute to the post-transcriptional regulation of specific mRNAs.
    Original languageEnglish
    Pages (from-to)6505-6514
    Number of pages10
    JournalThe EMBO Journal
    Issue number23
    Publication statusPublished - Dec 2002


    • AU-rich element
    • hnRNP
    • MAPKAP-K2
    • p38 MAP kinase
    • Lipopolysaccharide (LPS)


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