Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method.
The signaling network underlying eukaryotic chemosensing is a complex combination of receptor-mediated transmembrane signals, lipid modifications, protein translocations, and differential activation/deactivation of membrane-bound and cytosolic components. As such, it provides particularly interesting challenges for a combined computational and experimental analysis. We developed a novel detailed molecular signaling model that, when used to simulate the response to the attractant cyclic adenosine monophosphate (cAMP), made nontrivial predictions about Dictyostelium chemosensing. These predictions, including the unexpected existence of spatially asymmetrical, multiphasic, cyclic adenosine monophosphate-induced PTEN translocation and phosphatidylinositol-(3,4,5)P3 generation, were experimentally verified by quantitative single-cell microscopy leading us to propose significant modifications to the current standard model for chemoattractant-induced biochemical polarization in this organism. Key to this successful modeling effort was the use of "Simmune," a new software package that supports the facile development and testing of detailed computational representations of cellular behavior. An intuitive interface allows user definition of complex signaling networks based on the definition of specific molecular binding site interactions and the subcellular localization of molecules. It automatically translates such inputs into spatially resolved simulations and dynamic graphical representations of the resulting signaling network that can be explored in a manner that closely parallels wet lab experimental procedures. These features of Simmune were critical to the model development and analysis presented here and are likely to be useful in the computational investigation of many aspects of cell biology.
Meier-Schellersheim
Martin
M
Lymphocyte Biology Section and Program in Systems Immunology and Infectious Disease Modeling, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mms@niaid.nih.gov
Xu
Xuehua
X
Angermann
Bastian
B
Kunkel
Eric J
EJ
Jin
Tian
T
Germain
Ronald N
RN
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D000242:Cyclic AMP / Q000494:pharmacology*; D004023:Dictyostelium / Q000187:drug effects* / Q000378:metabolism*; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction
D018129:Phosphatidylinositol Phosphates; D015800:Protozoan Proteins; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase