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A Model for Direction Sensing in Dictyostelium discoideum: Ras Activity and Symmetry Breaking Driven by a Gβγ-Mediated, Gα2-Ric8 -- Dependent Signal Transduction Network | PLOS Computational Biology

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Author Summary Many eukaryotic cells, including Dictyostelium discoideum (Dicty), neutrophils and other cells of the immune system, can detect and reliably orient themselves in chemoattractant gradients. In Dicty, signal detection and transduction involves a G-protein-coupled receptor (GPCR) through which extracellular cAMP signals are transduced into Ras activation via an intermediate heterotrimeric G-protein (G α 2 β γ). Ras activation is the first polarized response to cAMP gradients in Dicty. Recent work has revealed mutiple new characteristics of Ras activation in Dicty, thereby providing new insights into direction sensing mechanisms and pointing to the need for new models of chemotaxis. Here we propose a novel reaction-diffusion model of Ras activation based on three major components: one involving the GPCR, one centered on G α 2 β γ, and one involving the monomeric G protein Ras. 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. We show that Ric8-modulated G α 2 β γ cycling between the cytosol and membrane can account for many of the observed responses in Dicty, including imperfect adaptation, multiple phases of Ras activity in a cAMP gradient, rectified directional sensing, and a solution to the back-of-the-wave problem.

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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 Gα2 βγ, 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 G α 2 β γ cycling modulated by Ric8, a nonreceptor guanine exchange factor for G α 2 in Dicty, drives multiple phases of Ras activation and leads to direction sensing and signal amplification in cAMP gradients. The model predicts that both G α 2 and Gβγ are essential for direction sensing, in that membrane-localized G α 2 *, the activated GTP-bearing form of G α 2, 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.

keywords

Cytosol,Signal amplification,Chemotaxis,Ras signaling,Cell membranes,G protein coupled receptors,Signal transduction,Signaling networks

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https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004900

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A Model for Direction Sensing in Dictyostelium discoideum: Ras Activity and Symmetry Breaking Driven by a Gβγ-Mediated, Gα2-Ric8 -- Dependent Signal Transduction Network

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Author Summary Many eukaryotic cells, including Dictyostelium discoideum (Dicty), neutrophils and other cells of the immune system, can detect and reliably orient themselves in chemoattractant gradients. In Dicty, signal detection and transduction involves a G-protein-coupled receptor (GPCR) through which extracellular cAMP signals are transduced into Ras activation via an intermediate heterotrimeric G-protein (G α 2 β γ). Ras activation is the first polarized response to cAMP gradients in Dicty. Recent work has revealed mutiple new characteristics of Ras activation in Dicty, thereby providing new insights into direction sensing mechanisms and pointing to the need for new models of chemotaxis. Here we propose a novel reaction-diffusion model of Ras activation based on three major components: one involving the GPCR, one centered on G α 2 β γ, and one involving the monomeric G protein Ras. 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. We show that Ric8-modulated G α 2 β γ cycling between the cytosol and membrane can account for many of the observed responses in Dicty, including imperfect adaptation, multiple phases of Ras activity in a cAMP gradient, rectified directional sensing, and a solution to the back-of-the-wave problem.

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https://journals.plos.org/ploscompbiol/article/figure/image?id=10.1371/journal.pcbi.1004900.g029&size=inline

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A Model for Direction Sensing in Dictyostelium discoideum: Ras Activity and Symmetry Breaking Driven by a Gβγ-Mediated, Gα2-Ric8 -- Dependent Signal Transduction Network

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A Model for Direction Sensing in Dictyostelium discoideum: Ras Activity and Symmetry Breaking Driven by a Gβγ-Mediated, Gα2-Ric8 -- Dependent Signal Transduction Network

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