Untangling the wires: A strategy to trace functional interactions in signaling and gene networks

Boris N. Kholodenko, Anatoly Kiyatkin, Frank J. Bruggeman, Eduardo Sontag, Hans V. Westerhoff, Jan B. Hoek

Research output: Contribution to journalArticlepeer-review

295 Scopus citations


Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. However, current methodologies for analysis do not permit interpretation of the data in ways that unravel cellular networking. We propose a quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level or applied within a "modular" framework, which dramatically decreases the number of variables to be assayed. This method is based on a mathematical derivation that demonstrates how the topology and strength of network connections can be retrieved from experimentally measured network responses to successive perturbations of all modules. Importantly, our analysis can reveal functional interactions even when the components of the system are not all known. Under these circumstances, some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated by using computer-generated responses of a modeled mitogen-activated protein kinase cascade and gene network.

Original languageEnglish (US)
Pages (from-to)12841-12846
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - Oct 1 2002

All Science Journal Classification (ASJC) codes

  • General

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