title: Design principles of nuclear receptor signaling: how complex networking improves signal transduction.
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.
authors.affiliation: Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Alexey N
authors.initials: AN
authors.lastname: Kolodkin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruggeman
authors.forename: Nick
authors.initials: N
authors.lastname: Plant
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Moné
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
authors.forename: Jacky L
authors.initials: JL
authors.lastname: Snoep
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015870:Gene Expression; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D022022:Nuclear Pore / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology
chemical_list: D028884:Karyopherins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D006160:Guanosine Triphosphate