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      Evolutionarily Conserved Coupling of Adaptive and Excitable Networks Mediates Eukaryotic Chemotaxis

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          Abstract

          Numerous models explain how cells sense and migrate toward shallow chemoattractant gradients. Studies show that an excitable signal transduction network acts as a pacemaker that controls the cytoskeleton to drive motility. Here we show that this network is required to link stimuli to actin polymerization and chemotactic motility and we distinguish the various models of chemotaxis. First, signaling activity is suppressed toward the low side in a gradient or following removal of uniform chemoattractant. Second, signaling activities display a rapid shut off and a slower adaptation during which responsiveness to subsequent test stimuli decline. Simulations of various models indicate that these properties require coupled adaptive and excitable networks. Adaptation involves a G-protein independent inhibitor since stimulation of cells lacking G-protein function suppresses basal activities. The salient features of the coupled networks were observed for different chemoattractants in Dictyostelium and in human neutrophils, suggesting an evolutionarily conserved mechanism for eukaryotic chemotaxis.

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          Defining network topologies that can achieve biochemical adaptation.

          Many signaling systems show adaptation-the ability to reset themselves after responding to a stimulus. We computationally searched all possible three-node enzyme network topologies to identify those that could perform adaptation. Only two major core topologies emerge as robust solutions: a negative feedback loop with a buffering node and an incoherent feedforward loop with a proportioner node. Minimal circuits containing these topologies are, within proper regions of parameter space, sufficient to achieve adaptation. More complex circuits that robustly perform adaptation all contain at least one of these topologies at their core. This analysis yields a design table highlighting a finite set of adaptive circuits. Despite the diversity of possible biochemical networks, it may be common to find that only a finite set of core topologies can execute a particular function. These design rules provide a framework for functionally classifying complex natural networks and a manual for engineering networks. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
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            Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration.

            Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. We use morphological perturbations, cell-severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, plasma membrane tension could serve as a long-range inhibitor in neutrophils. We find that membrane tension doubles during leading-edge protrusion, and increasing tension is sufficient for long-range inhibition of actin assembly and Rac activation. Furthermore, reducing membrane tension causes uniform actin assembly. We suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant source of long-range inhibition that constrains the spread of the existing front and prevents the formation of secondary fronts. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity.

              Chemotaxis, the directed migration of cells in chemical gradients, is a vital process in normal physiology and in the pathogenesis of many diseases. Chemotactic cells display motility, directional sensing, and polarity. Motility refers to the random extension of pseudopodia, which may be driven by spontaneous actin waves that propagate through the cytoskeleton. Directional sensing is mediated by a system that detects temporal and spatial stimuli and biases motility toward the gradient. Polarity gives cells morphologically and functionally distinct leading and lagging edges by relocating proteins or their activities selectively to the poles. By exploiting the genetic advantages of Dictyostelium, investigators are working out the complex network of interactions between the proteins that have been implicated in the chemotactic processes of motility, directional sensing, and polarity.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                10 September 2014
                27 October 2014
                2014
                27 April 2015
                : 5
                : 5175
                Affiliations
                [1 ]Department of Cell Biology, Johns Hopkins School of Medicine, 725 N. Wolfe Street WBSB 116, Baltimore, Maryland 21205, USA
                [2 ]Department of Electrical and Computer Engineering, Johns Hopkins University, 3400 N. Charles Street 226 Barton Hall, Baltimore, Maryland 21218, USA
                [3 ]Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, 138 Yi Xue Yuan Road, Shanghai, 200032, China
                Author notes
                [4 ]Correspondence should be addressed to P.N.D. ( pnd@ 123456jhmi.edu ) or C.H.H ( chuang29@ 123456jhmi.edu )
                Article
                NIHMS626542
                10.1038/ncomms6175
                4211273
                25346418
                3f419d2d-5b76-46fb-848e-1881d6607934
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