The annexin protein lipocortin 1 regulates the MAPK/ERK pathway

Lipocortin 1 (annexin 1) is a calcium- and phospholipid-binding protein tha t modulates anti-inflammatory responses including those induced by lipopoly saccharide. To investigate the precise role of lipocortin 1 in regulating t he lipopolysaccharide-induced signal transduction pathways, we generated st able RAW 264.7 macrophage cell lines expressing decreased and increased lip ocortin 1 protein. Several RAW 264.7 clones with increased lipocortin 1 pro tein levels showed constitutive activation of the mitogen-activated protein kinase extracellular signal-regulated kinase, which was down-regulated fol lowing lipopolysaccharide treatment. Conversely, clones with decreased lipo cortin 1 protein expression showed prolonged extracellular signal-regulated kinase activity, following lipopolysaccharide activation. Lipocortin 1 spe cifically regulates the components of the extracellular signal-regulated ki nase pathway, since changes in lipocortin 1 protein expression had no affec t on the related mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Lipocortin 1 modulated upstream components of the extracellular si gnal-regulated kinase pathway and associated with the adaptor protein growt h factor binding protein. The downstream consequences of altered extracellu lar signal-regulated kinase activity were independent of the proinflammator y transcription factor nuclear factor kappa B. These data indicate that Lip ocortin 1 specifically regulates proximal signaling components of the extra cellular signal-regulated kinase signal transduction pathway, resulting in the modulation of biochemical functions in RAW macrophages.