(398h) Complex Traveling Wave Phenomena Mediated By the Coupling of Phosphorylation Cascades and Extracellular Diffusion in Cellular Populations

MAPK phosphorylation cascades in cells exhibit steady state, bistable and oscillatory behavior. Oscillations of MAPK activity have been reported in several studies dealing with various cellular populations. The period of oscillations ranges from minutes to hours. It is assumed that the oscillatory and bistable phenomena serve as a specific response to cellular signaling in different stages of the development of tissues. However, their detail mechanism as well as origin is unknown.

Recently we have revealed a minimal reaction subnetwork in MAPK cascade that is responsible for the emergence of bistable and oscillatory behavior. The method of stoichiometric network analysis was used for the determination of the reaction core. It seems that the bistable and oscillatory phenomena arise from so called competitive autocatalysis inside the MAPK subnetwork.

Here we will present a possible mechanism that can serve for the propagation of specific MAPK activity in cellular populations. The intracellular MAPK subnetwork is coupled with ligand-receptor signaling processes in our model. Spatially one dimensional extracellular domain that allows for ligand diffusion, ligand release and ligand interaction with membrane receptors is considered. Ligand-receptor complexes formed on the cytosolic membrane represents an input to the MAPK cascade. It is assumed that a double-phosphorylated kinase of MAPK cascade activates a specific protease responsible for the ligand release into extracellular space and thus closes a feedback loop.

We will show that this coupling leads to the coexistence of one, two or three different steady states, or to the coexistence of a stable steady state and periodic solution. We systematically study the behavior of two identical cellular populations at the place of their contact. These populations differ only by initial conditions that are expressed as a particular stable steady state or periodic regime. We have found that traveling waves of MAPK activity typically appear at the place of contact. The propagation velocities and character strongly depend on the selected initial states of the two populations. The results of our systematic study and classification of the propagating waves will be presented.