Self-organization of the phosphatidylinositol lipids signaling system for random cell migration

Abstract

Phosphatidylinositol (PtdIns) lipids have been identified as key signaling mediators for random cell migration as well as chemoattractant-induced directional migration. However, how the PtdIns lipids are organized spatiotemporally to regulate cellular motility and polarity remains to be clarified. Here, we found that selforganized waves of PtdIns 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] are generated spontaneously on the membrane of Dictyostelium cells in the absence of a chemoattractant. Characteristic oscillatory dynamics within the PtdIns lipids signaling system were determined experimentally by observing the phenotypic variability of PtdIns lipid waves in single cells, which exhibited characteristics of a relaxation oscillator. The enzymes phosphatase and tensin homolog (PTEN) and phosphoinositide-3-kinase (PI3K), which are regulators for PtdIns lipid concentrations along the membrane, were essential for wave generation whereas functional actin cytoskeleton was not. Defects in these enzymes inhibited wave generation as well as actin-based polarization and cell migration. On the basis of these experimental results, we developed a reaction-diffusion model that reproduced the characteristic relaxation oscillation dynamics of the PtdIns lipid system, illustrating that a self-organization mechanism provides the basis for the PtdIns lipids signaling system to generate spontaneous spatiotemporal signals for random cell migration and that molecular noise derived from stochastic fluctuations within the signaling components gives rise to the variability of these spontaneous signals.phosphatase and tensin homolog | spontaneous polarization | relaxation oscillation | traveling wave | noise

Phase geometries of two-dimensional excitable waves govern self-organized morphodynamics of amoeboid cells

“…It should be emphasized that 2D geometry is essential for understanding dynamics of the observed pattern and their transitions. In earlier models based on one-dimensional geometry (6,15,30,36), a switch of patterns such as reversion of wave propagation along the cell periphery occurs merely by stochastic noise (6). The current study suggests that such a view of pattern transition in many cases could be an oversimplification, because topological charge of the spiral core is robust and cannot simply be flipped by random noise.…”

“…Because the observed wave geometries are generic (26), earlier models of PIP3/F-actin waves in Dictyostelium, whether they are abstract (19) or detailed (6,15), may also be able to capture some of the essential dynamics uncovered in this study. Future studies that include mutant analysis should allow comparison of details that delineate the existing models.…”

“…To address how the observed wave patterns arise from regulation of PIP3, we studied a simplified mathematical model that describes the essence of the phosphorylation/dephosphorylation reaction of the phosphoinositides and their diffusion at the basal membrane (15,30) (Fig. S4A; see SI Text for details).…”

Heterotrimeric G-protein shuttling via Gip1 extends the dynamic range of eukaryotic chemotaxis

“…In contrast to the spatial distributions of cAMP/cAR1 association and G-protein activation, downstream signaling pathways are activated in an extremely biased manner at the anterior or posterior of the cell (3,4). For example, localized patches of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) are generated at the plasma membrane by an intracellular signal transduction excitable network (STEN) and function as a cue to control the pseudopod formation of motile cells (9,10). Because PIP 3 patches have a relatively constant size of a few microns in diameter, this excitable mechanism can ensure a constant output of chemotactic responses over a wide range of concentrations.…”

Stochastic transitions in a bistable reaction system on the membrane

“…In stimulated thin neuronal protrusions, it has been observed that slowly diffusing autocatalytic CaMKII kinases exhibit pulsatile compartmentalized activity [36]; a spatially extended bistable system can spontaneously generate subregions, where different steady states dominate [37]. Self-organized foci of activity can generate activating travelling waves [38]. Propagation of waves can give rise to long-lasting cell polarity when the fast-diffusing inhibitor accumulates proportionally to the amount of slow-diffusing activated molecules so that the wavefront can be stalled.…”