Design principles of nuclear receptor signaling: How complex networking improves signal transduction

Alexey N. Kolodkin, Frank J. Bruggeman, Nick Plant, Martijn J. Moné, Barbara M. Bakker, Moray J. Campbell, Johannes P.T.M. Van Leeuwen, Carsten Carlberg, Jacky L. Snoep, Hans V. Westerhoff

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of design aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic nuclear receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands.

Original languageEnglish
Article number446
JournalMolecular Systems Biology
Volume6
DOIs
Publication statusPublished - 2010
Externally publishedYes

Keywords

  • biochemical network
  • kinetic model
  • nuclear receptor
  • signaling
  • systems biology

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