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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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      Most cited references 63

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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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        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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          Tumor suppressor PTEN mediates sensing of chemoattractant gradients.

          Shallow gradients of chemoattractants, sensed by G protein-linked signaling pathways, elicit localized binding of PH domains specific for PI(3,4,5)P3 at sites on the membrane where rearrangements of the cytoskeleton and pseudopod extension occur. Disruption of the PI 3-phosphatase, PTEN, in Dictyostelium discoideum dramatically prolonged and broadened the PH domain relocation and actin polymerization responses, causing the cells lacking PTEN to follow a circuitous route toward the attractant. Exogenously expressed PTEN-GFP localized to the surface membrane at the rear of the cell. Membrane localization required a putative PI(4,5)P2 binding motif and was required for chemotaxis. These results suggest that specific phosphoinositides direct actin polymerization to the cell's leading edge and regulation of PTEN through a feedback loop plays a critical role in gradient sensing and directional migration.
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            Author and article information

            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 )
            Journal
            101528555
            37539
            Nat Commun
            Nat Commun
            Nature communications
            2041-1723
            10 September 2014
            27 October 2014
            2014
            27 April 2015
            : 5
            : 5175
            25346418
            4211273
            10.1038/ncomms6175
            NIHMS626542
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