Modeling of feedback interactions between MAP kinase and cAMP signaling pathways

Abstract

Both the mitogen-activated protein kinase (MAPK) and cAMP signaling pathways play critical roles in cellular responses to external stimuli. Although many molecular interactions between these pathways have been identified, little is known about how such interactions shape the signals transmitted through these pathways. Here I present a theoretical model incorporating known feedback interactions between the MAPK and CAMP signaling pathways. In contrast to previous studies considering only the MAPK cascade, simulations made using this model suggest that, in the presence of feedback regulation from the cAMP signaling pathway, elements of the MAPK cascade do not necessarily behave in a bistable fashion. Rather, under constant stimulus conditions, interactions between these pathways can trigger slow oscillatory responses. Undoubtedly, other feedback interactions not considered here further influence both signaling pathways. Given the large number of interactions between MAPK, cAMP, and other signaling pathways (e.g., Ca/sup 2+/), it seems likely that oscillations in one pathway will trigger oscillations in several others. However, until better in vivo methods are developed for measuring enzyme activity and second messenger concentrations, we will be only be able to consider how information might be encoded within such oscillations.