Abstract: |
This paper describes a potential pitfall of perturbation-based approaches to network inference It is shows experimentally, and then explained mathematically, how even in the simplest signaling systems, perturbation methods may lead to paradoxical conclusions: for any given pair of two components X and Y, and depending upon the specific intervention on Y, either an activation or a repression of X could be inferred. The experiments are performed in an in vitro minimal system, thus isolating the effect and showing that it cannot be explained by feedbacks due to unknown intermediates; this system utilizes proteins from a pathway in mammalian (and other eukaryotic) cells that play a central role in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis and is a perturbation target of contemporary therapies for various types of cancers. The results show that the simplistic view of intracellular signaling networks being made up of activation and repression links is seriously misleading, and call for a fundamental rethinking of signaling network analysis and inference methods. |