Figure 2

Graphical representation of the model. The graphs are represented in Systems Biology Graphical Notation [51] as implemented in CellDesigner [50] version 4.2. A: The diagram shows the different states of each protein (rounded rectangles) and the possible state transitions (arrows). Catalysed transitions are depicted as lines from the catalyst to a circle at the state transition arrow. The model has two input nodes: ERK and JAK (white nodes). ERK is phosphorylating RSK1 (grey nodes). ERK and RSK1 are phosphorylating MITF (red nodes) at S73 (blue lines) and S409 (pink lines), respectively. MITF in different phosphorylation states combines (red lines) with PIAS3 (yellow nodes) forming complexes (orange grouping nodes). On the other side, JAK phosphorylates STAT3 (blue nodes), which is going into complex with PIAS3 when activated (green grouping node). The output nodes of the model are all the free MITF states and the phosphorylated STAT3. Communication between the ERK-RSK-MITF pathway and the JAK-STAT pathway via the competitive binding to free PIAS3 is the topic of this work. B: Production and degradation. The amounts of phosphorylated ERK and JAK are represented by constants. The total amount of RSK1 is constant while the phosphorylation state is dynamically determined. The amounts of MITF, PIAS3 and STAT3 are dynamically determined by the production and degradation of the proteins. The broken arrows from the genes (yellow rectangles) to the proteins represent production, while arrows from the proteins to the degradation node (red filled empty set symbol) represent degradation. C: Ubiquitination of MITF. All S73 phosphorylated MITF can be ubiquitin tagged, in which case it will eventually be degraded. The ubiquitination is catalysed by phosphorylated ERK.