The Dynactome-investigating dynamic network motifs of kinasess

Network motifs of kinases phosphorylating other kinases represent a unique control system for cellular functions. Recently, we described the bioinformatics tool NetworKIN (Linding et al, Cell in press) which accurately predicts kinase-substrate pairs. With these predicted feedback and feed-forward motifs of kinases, we characterize their effect through over-expression and monitoring of the phosphorylation of downstream signalling targets, such as MAP kinases. To understand the behaviour of this system in signal integration and cellular decision-making, we stimulate cells over-expressing a kinase with orthogonal signals, such as apoptosis promoting vs. growth-inducing cytokines, allowing for a more comprehensive coverage of signalling space (Janes et al., Science 2005). We present some feedback and feed-forward motifs found in the kinase-kinase network, and describe efforts to characterize dynamic phosphorylation sites in the context of orthogonal signals.