Signaling pathways in context

The last decade has seen a rise in the development of methods and models to analyze cellular networks on all levels. The applications of this knowledge are, however, often confined to specifics of the network in concrete conditions and leveraging it is hampered by the lack of information about this context and its implications on the system. While not all cellular networks have been deciphered yet, even for well-studied networks their versatility in different contexts is barely considered. Here, we focus on challenges and potentials when integrating signaling networks into their encompassing structures. We highlight three different consequences of this process: a) its fundamental importance for whole-cell and large-scale models, b) significant changes in contextual behavior imposed on entire systems by genetic variations, and c) species-specific conservation or divergence of signaling motifs can give important clues on how to handle cellular context. While important studies have been conducted on these topics to some extent, an increased focus on developing and exploiting solutions for integrative contextualization should turn out as a fruitful path for both theoretical and experimental research.