Abstract
Chemotaxis is a dynamic cellular process, comprised of direction sensing, polarization and locomotion, that leads to the directed movement of eukaryotic cells along extracellular gradients. As a primary step in the response of an individual cell to a spatial stimulus, direction sensing has attracted numerous theoretical treatments aimed at explaining experimental observations in a variety of cell types. Here we propose a new model of direction sensing based on experiments using Dictyostelium discoideum (Dicty). The model is built around a reaction-diffusion-translocation system that involves three main component processes: a signal detection step based on G-protein-coupled receptors (GPCR) for cyclic AMP (cAMP), a transduction step based on a heterotrimetic G protein Gα2βγ, and an activation step of a monomeric G-protein Ras. The model can predict the experimentally-observed response of cells treated with latrunculin A, which removes feedback from downstream processes, under a variety of stimulus protocols. We show that cycling modulated by Ric8, a nonreceptor guanine exchange factor for in Dicty, drives multiple phases of Ras activation and leads to direction sensing and signal amplification in cAMP gradients. The model predicts that both and Gβγ are essential for direction sensing, in that membrane-localized , the activated GTP-bearing form of , leads to asymmetrical recruitment of RasGEF and Ric8, while globally-diffusing Gβγ mediates their activation. We show that the predicted response at the level of Ras activation encodes sufficient ‘memory’ to eliminate the ‘back-of-the wave’ problem, and the effects of diffusion and cell shape on direction sensing are also investigated. In contrast with existing LEGI models of chemotaxis, the results do not require a disparity between the diffusion coefficients of the Ras activator GEF and the Ras inhibitor GAP. Since the signal pathways we study are highly conserved between Dicty and mammalian leukocytes, the model can serve as a generic one for direction sensing.
Highlights
Many eukaryotic cells can detect both the magnitude and direction of extracellular signals using receptors embedded in the cell membrane
In Dicty, signal detection and transduction involves a G-protein-coupled receptor (GPCR) through which extracellular cyclic AMP (cAMP) signals are transduced into Ras activation via an intermediate heterotrimeric G-protein (Ga2bg)
In contrast to existing local excitation, global inhibition (LEGI) models of direction sensing, in which a fast-responding but slowly-diffusing activator and a slow-acting rapidly diffusing inhibitor set up an internal gradient of activity, our model is based on equal diffusion coefficients for all cytosolic species, and the unbalanced local sequestration of some species leads to gradient sensing and amplification
Summary
Many eukaryotic cells can detect both the magnitude and direction of extracellular signals using receptors embedded in the cell membrane. Direction sensing refers to the molecular mechanism that detects the gradient and generates an internal amplified response, providing an internal compass for the cell [11]. Polarization involves the establishment of an asymmetric shape with a well-defined anterior and posterior, a semi-stable state that allows a cell to move in the same direction without an external stimulus. These three processes are linked through interconnected networks that govern (i) receptormediated transduction of an extracellular signal into a primary intracellular signal, (ii) translation of the primary signal into pathway-specific signals for one or more signalling pathways, and (iii) the actin cytoskeleton and auxiliary proteins that determine polarity of the cell. A single extracellular signal may activate numerous pathways, but our focus is on the first pathway, which involves transduction of an extracellular cAMP signal via a GPCR, and one specific pathway of the second type, the Ras pathway, which is involved in activating the appropriate downstream networks that govern chemotactic locomotion
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