Cells navigate with a local-excitation, global-inhibition-biased excitable network

Cells have an internal compass that enables them to move along shallow chemical gradients. As amoeboid cells migrate, signaling events such as Ras and PI3K activation occur spontaneously on pseudopodia. Uniform stimuli trigger a symmetric response, whereupon cells stop and round up; then localized p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-10, Vol.107 (40), p.17079-17086
Main Authors: Xiong, Yuan, Huang, Chuan-Hsiang, Iglesias, Pablo A., Devreotes, Peter N.
Format: Article
Language:English
Subjects:
Actins
Animals
Biological Sciences
Cell adhesion & migration
Cell motility
Cells
Chemotactic factors
Chemotactic Factors - metabolism
Chemotaxis
Chemotaxis - physiology
Control loops
Cytoskeleton
Dictyostelium - cytology
Dictyostelium - physiology
Germ cells
Humans
Mental stimulation
Metastasis
Models, Biological
Mutation
Neutrophils
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Physiological regulation
ras Proteins - genetics
ras Proteins - metabolism
Reaction kinetics
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Signal Transduction - physiology
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Summary:Cells have an internal compass that enables them to move along shallow chemical gradients. As amoeboid cells migrate, signaling events such as Ras and PI3K activation occur spontaneously on pseudopodia. Uniform stimuli trigger a symmetric response, whereupon cells stop and round up; then localized patches of activity appear as cells spread. Finally cells adapt and resume random migration. In contrast, chemotactic gradients continuously direct signaling events to the front of the cell. Local-excitation, global-inhibition (LEGI) and reaction—diffusion models have captured some of these features of chemotaxing cells, but no system has explained the complex response kinetics, sensitivity to shallow gradients, or the role of recently observed propagating waves within the actin cytoskeleton. We report here that Ras and PI3K activation move in phase with the cytoskeleton events and, drawing on all of these observations, propose the LEGI-biased excitable network hypothesis. We formulate a model that simulates most of the behaviors of chemotactic cells: In the absence of stimulation, there are spontaneous spots of activity. Stimulus increments trigger an initial burst of patches followed by localized secondary events. After a few minutes, the system adapts, again displaying random activity. In gradients, the activity patches are directed continuously and selectively toward the chemoattractant, providing an extraordinary degree of amplification. Importantly, by perturbing model parameters, we generate distinct behaviors consistent with known classes of mutants. Our study brings together heretofore diverse observations on spontaneous cytoskeletal activity, signaling responses to temporal stimuli, and spatial gradient sensing into a unified scheme.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1011271107