Signaling cascades as cellular devices for spatial computations.
Signaling networks usually include protein-modification cycles. Cascades of such cycles are the backbones of multiple signaling pathways. Protein gradients emerge from the spatial separation of opposing enzymes, such as kinases and phosphatases, or guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) for GTPase cycles. We show that different diffusivities of an active protein form and an inactive form leads to spatial gradients of protein abundance in the cytoplasm. For a cascade of cycles, using a discrete approximation of the space, we derive an analytical expression for the spatial gradients and show that it converges to an exact solution with decreasing the size of the quantization. Our results facilitate quantitative analysis of the dependence of spatial gradients on the network topology and reaction kinetics. We demonstrate how different cascade designs filter and process the input information to generate precise, complex spatial guidance for multiple GTPase effector processes. Thus, protein-modification cascades may serve as devices to compute complex spatial distributions of target proteins within intracellular space.
Stelling
Jörg
J
Institute of Computational Science and Swiss Institute of Bioinformatics, ETH Zurich, 8092, Zurich, Switzerland. joerg.stelling@inf.ethz.ch
Kholodenko
Boris N
BN
D003198:Computer Simulation; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction
D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors