title: Modeling the signaling endosome hypothesis: why a drive to the nucleus is better than a (random) walk.
abstract: BACKGROUND
  Information transfer from the plasma membrane to the nucleus is a universal cell biological property. Such information is generally encoded in the form of post-translationally modified protein messengers. Textbook signaling models typically depend upon the diffusion of molecular signals from the site of initiation at the plasma membrane to the site of effector function within the nucleus. However, such models fail to consider several critical constraints placed upon diffusion by the cellular milieu, including the likelihood of signal termination by dephosphorylation. In contrast, signaling associated with retrogradely transported membrane-bounded organelles such as endosomes provides a dephosphorylation-resistant mechanism for the vectorial transmission of molecular signals. We explore the relative efficiencies of signal diffusion versus retrograde transport of signaling endosomes.
  
  
  RESULTS
  Using large-scale Monte Carlo simulations of diffusing STAT-3 molecules coupled with probabilistic modeling of dephosphorylation kinetics we found that predicted theoretical measures of STAT-3 diffusion likely overestimate the effective range of this signal. Compared to the inherently nucleus-directed movement of retrogradely transported signaling endosomes, diffusion of STAT-3 becomes less efficient at information transfer in spatial domains greater than 200 nanometers from the plasma membrane.
  
  
  CONCLUSIONS
  Our model suggests that cells might utilize two distinct information transmission paradigms: 1) fast local signaling via diffusion over spatial domains on the order of less than 200 nanometers; 2) long-distance signaling via information packets associated with the cytoskeletal transport apparatus. Our model supports previous observations suggesting that the signaling endosome hypothesis is a subset of a more general hypothesis that the most efficient mechanism for intracellular signaling-at-a-distance involves the association of signaling molecules with molecular motors that move along the cytoskeleton. Importantly, however, cytoskeletal association of membrane-bounded complexes containing ligand-occupied transmembrane receptors and downstream effector molecules provides the ability to regenerate signals at any point along the transmission path. We conclude that signaling endosomes provide unique information transmission properties relevant to all cell architectures, and we propose that the majority of relevant information transmitted from the plasma membrane to the nucleus will be found in association with organelles of endocytic origin.
authors.affiliation: Departments of Neuroscience and Neurology, Mayo Clinic College of Medicine, Guggenheim 442-C, Rochester, MN 55905, USA. howe.charles@mayo.edu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Howe
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D003198:Computer Simulation; D004058:Diffusion; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor