Immediate early gene activation upon mitogenic activation occurs through the serum response element (SRE), which makes the delineation of the upstream pathways a powerful means to engineer cellular responses. The malfunctioning of this system leads to a variety of disorders, ranging from neurological disorders such as Coffin-Lowry syndrome (RSK2 mutations) to cancer (c-fos mutations). We therefore investigated the SRE activation mechanism in a typical mammalian cell. Mitogenic Signaling uses the mitogen-activated protein kinase (MAPK) module through increased binding of the ternary complex factor (TCF), such as Elk-1, to the promoter DNA (the SRE element) and subsequent transcriptional activation, as well as through activation of a histone kinase, such as the MAPK-activated protein kinase (MAPKAP-K) ribosomal S6 kinase (RSK2). This computational model uses the biochemical simulation environment GEPASI 3.30 to investigate three major models of interaction for Elk-1 and RSK2, and to study the effect of histone acetyl transferase (HAT) recruitment in each of these models on the local chromatin modifications in the presence and absence of MAPK activation. We show that the quickest response on the chromatin can be achieved in the presence of a preformed complex of RSK2, Elk-1 and HAT, with HAT being activated upon dissociation from the complex upon activation of the MAPK cascade. This study presents critical components in the pathway that can be targeted for engineering of specific inhibitors or activators of the system. (C) 2004 Wiley Periodicals, Inc.