Endocytosis and Signaling: Competition of Rab Proteins
published: Nov. 27, 2007, recorded: October 2007, views: 1011
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Endocytosis and signaling are tightly linked. A dynamic network of subcellular compartments, termed endosomes, actively controls signal propagation, amplitude and timing by uptake and transport of membrane-associated signaling molecules. The small GTPase Rab5 is the central organizer of the protein machinery that assembles on early endosomes, providing a unique identity to the compartment that controls cargo sorting, transport and signaling potential. We interlink experimental and computational approaches to (I) unravel the design principles underlying the function and regulation of the endocytic pathway and to (II) understand the molecular links that govern endosomal control of signaling events. Our approach takes into account both newly identified Rab5 effectors as well as the perspective of an on-going genome-wide RNAi screening for novel endocytic transport regulators. We develop and analyze a mathematical core model of the kinetic interactions between the endosomal organizers Rab4, Rab5 and Rab7. The values of the model parameters are estimated from literature and FRAP experiments. Simulations and bifurcation analysis of the model reveal bistable behavior of Rab5 versus Rab7 dominance that reproduces the controled and robust transition from early to late endosomal compartments as observed by means of computational motion tracking of individual endosomes in fluorescence live cell imaging data.The modeled Rab5 module serves as a blueprint for the sequential assembly of the endocytic pathway, therewith contributing an important spatial aspect to systems biology. Our kinetic model explains the experimentally observed transitions between endosomal compartments as the result of cargo-regulated competition between Rab proteins.
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