Editorial overview: Membrane traffic and cell polarity

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Traffic control: p120-catenin acts as a gatekeeper to control the fate of classical cadherins in mammalian cells

Proteins of the p120 family have been implicated in the regulation of cadherin-based cell adhesion, but their relative importance in this process and their mechanism of action have remained less clear. Three papers in this issue suggest that p120 plays a key role in maintaining normal levels of cadherin in mammalian cells, and that it may do so by regulating cadherin trafficking (Chen et al., 2003; Davis et al., 2003; Xiao et al., 2003)

Doing cell biology in embryos: regulated membrane traffic and its implications for cadherin biology

Regulated trafficking of cadherin adhesion molecules is often invoked as a mechanism to generate dynamic adhesive cell-cell contacts for tissue modeling and morphogenesis. The past 2-3 years have seen several important papers that tackle the cell biology of cadherin trafficking in organismal systems to provide new insights into both mechanism and morphogenetic impact

Cycling Rho for tissue contraction

Cell contractility, driven by the RhoA GTPase, is a fundamental determinant of tissue morphogenesis. In this issue, Mason et al. (2016. J. Cell Biol http://dx.doi.org/10.1083/jcb.201603077) reveal that cyclic inactivation of RhoA, mediated by its antagonist, C-GAP, is essential for effective contractility to occur

Direct cadherin-activated cell signaling: a view from the plasma membrane

Classical cadherin adhesion molecules are key determinants of cell recognition and tissue morphogenesis, with diverse effects on cell behavior. Recent developments indicate that classical cadherins are adhesion-activated signaling receptors. In particular, early–immediate Rac signaling is emerging as a mechanism to coordinate cadherin–actin integration at the plasma membrane

Contact inhibition of locomotion and mechanical cross-talk between cell-cell and cell-substrate adhesion determines the pattern of junctional tension in epithelial cell aggregates

We generated a computational approach to analyze the biomechanics of epithelial cell aggregates, either island or stripes or entire monolayers, that combines both vertex and contact-inhibition-of-locomotion models to include both cell-cell and cell-substrate adhesion. Examination of the distribution of cell protrusions (adhesion to the substrate) in the model predicted high order profiles of cell organization that agree with those previously seen experimentally. Cells acquired an asymmetric distribution of basal protrusions, traction forces and apical aspect ratios that decreased when moving from the edge to the island center. Our in silico analysis also showed that tension on cell-cell junctions and apical stress is not homogeneous across the island. Instead, these parameters are higher at the island center and scales up with island size, which we confirmed experimentally using laser ablation assays and immunofluorescence. Without formally being a 3-dimensional model, our approach has the minimal elements necessary to reproduce the distribution of cellular forces and mechanical crosstalk as well as distribution of principal stress in cells within epithelial cell aggregates. By making experimental testable predictions, our approach would benefit the mechanical analysis of epithelial tissues, especially when local changes in cell-cell and/or cell-substrate adhesion drive collective cell behavior.Comment: 39 pages, 8 Figures. Supplementary Information is include

Instantaneous Segmental Energy Symmetry Index as Gait Compensation Indicator in Asymmetrical Walking

Purpose: Human body constantly adapts to optimise the energy expenditure. A better understanding of the mechanical energetic costs in lower extremities helps identify the compensatory mechanism adopted in asymmetrical gait. This paper proposes the use of instantaneous segmental energy and normalised symmetry index (SInorm) to examine asymmetrical gait. This approach can provide better overview of gait quality allowing identification of change in segmental energy during different gait phases and contribution of each segment in compensating abnormal walking. Method: An experimental study was carried out to validate this method. Twenty healthy subjects were recruited. Asymmetrical gait was simulated by restricting knee motion during walking using a knee brace. Mechanical energy was determined for each segment of the left and right limbs. Normalised Symmetry Index (SInorm) was then calculated to examine bilateral differences in segmental energy during stance phase and swing phase. Statistical analysis using ANOVA and Tukey-Kramer multiple comparison test to identify asymmetry of the segmental energy (p-value < 0.05). Result: Significant asymmetry of segmental energy occurred during swing phase. Greater asymmetry was observed in kinetic energy than in potential energy. The affected limb segments produced lower kinetic energy than the normal limb. At asymmetrical state, potential energy of the affected limb’s foot and thigh were lower than that of the normal segments while the inverse was true for thigh segment. Conclusion: These results suggested that in asymmetrical gait, a form of compensatory mechanism is adopted to walk. This can be observed in the change of instantaneous segmental energy during walking

Myosin VI and vinculin cooperate during the morphogenesis of cadherin cell–cell contacts in mammalian epithelial cells

Cooperation between cadherins and the actin cytoskeleton controls many aspects of epithelial biogenesis. We report here that myosin VI critically regulates the morphogenesis of epithelial cell–cell contacts. As epithelial monolayers mature in culture, discontinuous cell–cell contacts are initially replaced by continuous (cohesive) contacts. Myosin VI is recruited to cell contacts as they become linear and cohesive, where it forms a biochemical complex with epithelial cadherin (E-cadherin). Myosin VI is necessary for strong cadherin adhesion, for cells to form cohesive linear contacts, and for the integrity of the apical junctional complex. We find that vinculin mediates this effect of myosin VI. Myosin VI is necessary for vinculin and E-cadherin to interact. A combination of gain and loss of function approaches identifies vinculin as a downstream effector of myosin VI that is necessary for the integrity of intercellular contacts. We propose that myosin VI and vinculin form a molecular apparatus that generates cohesive cell–cell contacts in cultured mammalian epithelia

Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

Pathogens can alter epithelial polarity by recruiting polarity proteins to the apical membrane, but how a change in protein localization is linked to polarity disruption is not clear. In this study, we used chemically induced dimerization to rapidly relocalize proteins from the cytosol to the apical surface. We demonstrate that forced apical localization of Par3, which is normally restricted to tight junctions, is sufficient to alter apical membrane identity through its interactions with phosphatidylinositol 3-kinase (PI3K) and the Rac1 guanine nucleotide exchange factor Tiam1. We further show that PI3K activity is required upstream of Rac1, and that simultaneously targeting PI3K and Tiam1 to the apical membrane has a synergistic effect on membrane remodeling. Thus, Par3 coordinates the action of PI3K and Tiam1 to define membrane identity, revealing a signaling mechanism that can be exploited by human mucosal pathogens