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Nat Commun. 2017 Jul 10;8:16009. doi: 10.1038/ncomms16009.

Crosstalk and the evolvability of intracellular communication.

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US Army Engineer Research and Development Center, 3909 Halls Ferry Road, Vicksburg, Mississippi 39180, USA.
Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee 37830, USA.
University of Kansas, 2030 Becker Dr Lawrence, Kansas 66047, USA.
Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas 66047, USA.
Santa Fe Institute, 1399 Hyde Park Rd., Santa Fe, New Mexico 87501, USA.


Metazoan signalling networks are complex, with extensive crosstalk between pathways. It is unclear what pressures drove the evolution of this architecture. We explore the hypothesis that crosstalk allows different cell types, each expressing a specific subset of signalling proteins, to activate different outputs when faced with the same inputs, responding differently to the same environment. We find that the pressure to generate diversity leads to the evolution of networks with extensive crosstalk. Using available data, we find that human tissues exhibit higher levels of diversity between cell types than networks with random expression patterns or networks with no crosstalk. We also find that crosstalk and differential expression can influence drug activity: no protein has the same impact on two tissues when inhibited. In addition to providing a possible explanation for the evolution of crosstalk, our work indicates that consideration of cellular context will likely be crucial for targeting signalling networks.

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