Lipid domain–dependent regulation of single-cell wound repair

Vaughan, Emily M.; You, Jae‐Sung; Yu, Hoi-Ying Elsie; Lasek, Amber; Vitale, Nicolas; Hornberger, Troy A.; Bement, William M.

doi:10.1091/mbc.e14-03-0839

Cited by 61 publications

(70 citation statements)

References 47 publications

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“…Much like the canonical polarity response preceding chemotaxis [34,35], cell wound repair requires proper localization of small Rho GTPases (Cdc42 and Rho in this case) to direct cytoskeleton assembly and contraction. The approximate analytical and numerical methods described here, in combination with biological experiments [18,22,24,36] have been essential to understanding the molecular mechanisms regulating the repair response.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, this modelling predicted that positive feedback of Cdc42 onto its own activation is essential to the process. Finally, our modelling [9] in combination with experimental manipulations [24] reveal specific roles of two GTPase effectors, PKCb and PKCh. Based on semi-quantitative observations of how background and zone intensities change when these effectors are overexpressed (OE) or depressed (DN), we were able to rule out some plausible mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Observations (O3)-(O4) however require us to revise this and take a more sophisticated view of how its spatial distribution influences zone formation. Imaging indicates that PKCh is spatially graded with the highest concentration near the wound edge [24]. To determine how this spatial distribution might influence zone formation, we analysed the joint dependence of steady states for Rho (green) and Cdc42 (red) on the parameter h (figure 4c).…”

Section: Rsfsroyalsocietypublishingorg Interface Focus 6: 20160032mentioning

confidence: 99%

“…A schematic of the basic system is shown in figure 2. More recently, there has been evidence for lipid-dependent regulation of the wounds [24]. Of particular interest has been the involvement of the antagonistic protein kinases eta and beta (PKC b and h) [9,25].…”

Section: Introductionmentioning

confidence: 99%

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A mathematical model of GTPase pattern formation during single-cell wound repair

2016

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Rho GTPases are regulatory proteins whose patterns on the surface of a cell affect cell polarization, cell motility and repair of single-cell wounds. The stereotypical patterns formed by two such proteins, Rho and Cdc42, around laser-injured frog oocytes permit experimental analysis of GTPase activation, inactivation, segregation and crosstalk. Here, we review the development and analysis of a spatial model of GTPase dynamics that describe the formation of concentric zones of Rho and Cdc42 activity around wounds, and describe how this model has provided insights into the roles of the GTPase effector molecules protein kinase C (PKCβ and PKCη) and guanosine nucleotide dissociation inhibitor (GDI) in the wound response. We further demonstrate how the use of a ‘sharp switch’ model approximation in combination with bifurcation analysis can aid mapping the model behaviour in parameter space (approximate results confirmed with numerical simulation methods). Using these methods in combination with experimental manipulation of PKC activity (PKC overexpression (OE) and dominant negative conditions), we have shown that: (i) PKCβ most probably acts by enhancing existing positive feedbacks (from Rho to itself via the guanosine nucleotide exchange factor domain of Abr, and from Cdc42 to itself), (ii) PKCη most probably increases basal rates of inactivation (or possibly decreases basal rates of activation) of Rho and Cdc42, and (iii) the graded distribution of PKCη and its effect on initial Rho activity accounts for inversion of zones in a fraction (20%) of PKCη OE cells. Finally, we speculate that GDIs (which sequester GTPases) may have a critical role in defining the spatial domain, where the wound response may occur. This paper provides a more thorough exposition of the methods of analysis used in the investigation, whereas previous work on this topic was addressed to biologists and abbreviated such discussion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rsfsroyalsocietypublishingorg Interface Focus 6: 20160032mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A mathematical model of GTPase pattern formation during single-cell wound repair

2016

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“…Cell damage disrupts normal membrane lipid polarization and organization, and the plasma membrane surrounding the wound is further modified by transient de novo synthesis or the transport and delivery of different lipids, at specific areas of, or around the wound site [61].…”

Section: Dynamic Changes Of the Plasmalemma As Damage Signalsmentioning

confidence: 99%

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

Boucher

Mandato

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Wounding leads not only to plasma membrane disruption, but also to compromised cytoskeleton structures. This results not only in unwarranted exchanges between the cytosol and extracellular milieu, but also in loss of tensegrity, which may further endanger the cell. Tensegrity can be described as the interplay between the tensile forces generated by the apparent membrane tension, actomyosin contraction, and the cytoskeletal structures resisting those changes (e.g., microtubules). It is responsible for the structural integrity of the cell and for its ability to sense mechanical signals. Recent reviews dealing with single-cell healing mostly focused on the molecular machineries controlling the traffic and fusion of specific vesicles, or their role in different pathologies. In this review, we aim to take a broader view of the different modes of single cell repair, while focussing on the different ways the changes in plasmalemma surface area and composition, plasmalemma tension, and cytoskeletal dynamics may influence and affect single-cell repair.

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Regulation and Assembly of Actomyosin Contractile Rings in Cytokinesis and Cell Repair

Dekraker

Boucher

Mandato

2018

The Anatomical Record

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Cytokinesis and single‐cell wound repair both involve contractile assemblies of filamentous actin (F‐actin) and myosin II organized into characteristic ring‐like arrays. The assembly of these actomyosin contractile rings (CRs) is specified spatially and temporally by small Rho GTPases, which trigger local actin polymerization and myosin II contractility via a variety of downstream effectors. We now have a much clearer view of the Rho GTPase signaling cascade that leads to the formation of CRs, but some factors involved in CR positioning, assembly, and function remain poorly understood. Recent studies show that this regulation is multifactorial and goes beyond the long‐established Ca2+‐dependent processes. There is substantial evidence that the Ca2+‐independent changes in cell shape, tension, and plasma membrane composition that characterize cytokinesis and single‐cell wound repair also regulate CR formation. Elucidating the regulation and mechanistic properties of CRs is important to our understanding of basic cell biology and holds potential for therapeutic applications in human disease. In this review, we present a primer on the factors influencing and regulating CR positioning, assembly, and contraction as they occur in a variety of cytokinetic and single‐cell wound repair models. Anat Rec, 301:2051–2066, 2018. © 2018 Wiley Periodicals, Inc.

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Lipid domain–dependent regulation of single-cell wound repair

Cited by 61 publications

References 47 publications

A mathematical model of GTPase pattern formation during single-cell wound repair

A mathematical model of GTPase pattern formation during single-cell wound repair

Plasma membrane and cytoskeleton dynamics during single-cell wound healing

Regulation and Assembly of Actomyosin Contractile Rings in Cytokinesis and Cell Repair

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