The role of the p38 MAP kinase substrate, MAPKAPK-2 in proinflammatory cytokine signalling

Lumb, Simon (2001). The role of the p38 MAP kinase substrate, MAPKAPK-2 in proinflammatory cytokine signalling. PhD thesis The Open University.



The pro-inflammatory cytokine IL-1 induces the synthesis of many genes during inflammation. The signalling mechanisms triggered by IL-1 include activation of several distinct parallel MAP kinase pathways. The p38 MAP kinase pathway is activated particularly strongly by this cytokine. MAPKAP kinase-2 (MAPKAPK-2) is one of several p38 substrates that are regulated by direct phosphorylation. Few MAPKAPK-2 substrates are known. One of these, the small heat shock protein 27 (Hsp27), is rapidly phosphorylated following MAPKAPK-2 activation. In an attempt to delineate the role of MAPKAPK-2 in IL-1 signalling, IL-1 a induced MAPKAPK-2 activity was inhibited by stable overexpression of dominant negative (MAPKAPK-2 K93R) and MAPKAPK-2 anti-sense RNA (MAPKAPK-2 A/S) in HeLa cells. IL-1 a strongly induced COX-2 protein in empty vector transfected cells. In contrast MAPKAPK-2 K93R and MAPKAPK-2 A/S overexpressing cells strongly inhibited COX-2 protein and mRNA In addition IL-la induced IL-6 synthesis was also strongly inhibited by MAPKAPK-2 A/S. These results suggest that MAPKAPK-2 may act as an effector molecule involved in IL-la induced COX-2 and IL-6 synthesis. In an attempt to identify new MAPKAPK-2 substrates, yeast two-hybrid screening of a human leukocyte cDNA library identified a novel protein interaction between MAPKAPK-2 K93R and a close homologue of the human polyhomeotic 2 (HPH2) protein.

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