The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells

Analysing the signalling events following stimulation of mouse embryonic stem cells with serum and lysophosphatidic acid, we show that the extracellular signal-regulated kinase (ERK) pathway is involved in mediating c-fos induction. We demonstrate that the ERK-activated kinase MSK1 is required for full c-fos promoter activation, as well as for the phosphorylation of cAMP-responsive element (CRE) binding proteins. We propose that MSK1 contributes to ERK-mediated c-fos promoter activation by targeting CRE binding proteins.These results show that MSK1 is an important ERK-activated mediator of mitogen-stimulated c-fos induction. In addition, they indicate that MSK1 could act through CRE binding proteins to achieve c-fos promoter activation. Thus, they further our understanding of the complex regulation of the model immediate-early gene c-fos.Lysophosphatidic acid (LPA) is an intercellular mediator involved in inflammation and wound healing [1]. It is released by activated platelets and leukocytes, and is one of the most potent mitogens found in serum. LPA acts through G-protein-coupled receptors to activate a number of intracellular signalling pathways including mitogen-activated protein (MAP) kinase cascades and Rho signalling. This leads to cellular responses such as proliferation, differentiation and suppression of apoptosis. One way in which these effects are mediated is induction of immediate-early genes such as c-fos.The c-fos promoter has been extensively studied as a model for signal-activated gene induction [2,3]. It contains several regulatory elements, namely a serum response element (SRE), a cAMP-responsive element (CRE), a sis-inducible element, and an AP-1-like site, which serve to integrate input from a host of signalling pathways. These promoter elements are strongly interdependent. Mutation of one of them inhibits c-fos activation through any of the other elements, suggesting that they are connected by protein complexes [4].The c-fos SRE is constitutive