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NPJ Syst Biol Appl. 2019 May 23;5:19. doi: 10.1038/s41540-019-0096-1. eCollection 2019.

Mapping connections in signaling networks with ambiguous modularity.

Author information

1Institute of Physics, University of Freiburg, Freiburg, Germany.
2Systems Biology Ireland, University College Dublin, Dublin, Ireland.
3School of Mathematics and Statistics, University College Dublin, Dublin, Ireland.
4BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
5Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland.
6School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
7Department of Pharmacology, Yale University School of Medicine, New Haven, CT USA.
Contributed equally


Modular Response Analysis (MRA) is a suite of methods that under certain assumptions permits the precise reconstruction of both the directions and strengths of connections between network modules from network responses to perturbations. Standard MRA assumes that modules are insulated, thereby neglecting the existence of inter-modular protein complexes. Such complexes sequester proteins from different modules and propagate perturbations to the protein abundance of a downstream module retroactively to an upstream module. MRA-based network reconstruction detects retroactive, sequestration-induced connections when an enzyme from one module is substantially sequestered by its substrate that belongs to a different module. Moreover, inferred networks may surprisingly depend on the choice of protein abundances that are experimentally perturbed, and also some inferred connections might be false. Here, we extend MRA by introducing a combined computational and experimental approach, which allows for a computational restoration of modular insulation, unmistakable network reconstruction and discrimination between solely regulatory and sequestration-induced connections for a range of signaling pathways. Although not universal, our approach extends MRA methods to signaling networks with retroactive interactions between modules arising from enzyme sequestration effects.


Applied mathematics; Biochemical networks; Computer modelling

Conflict of interest statement

Competing interestsThe authors declare no competing interests.

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