Actin Dynamics at the Leading Edge: From Simple Machinery to Complex Networks

Insall, Robert H.; Machesky, Laura M.

doi:10.1016/j.devcel.2009.08.012

Cited by 378 publications

(366 citation statements)

References 123 publications

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“…2009), a Rho GTPase closely associated with the elaboration of these cellular extensions (Install and Machesky 2009; Ridley 2011). Consistent with previous published data (Cao et al.…”

Section: Resultsmentioning

confidence: 99%

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Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

et al. 2016

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Platelet endothelial cell adhesion molecule (PECAM‐1) has been implicated in angiogenesis through processes that involve stimulation of endothelial cell motility. Previous studies suggest that PECAM‐1 tyrosine phosphorylation mediates the recruitment and then activation of the tyrosine phosphatase SHP‐2, which in turn promotes the turnover of focal adhesions and the extension of filopodia, processes critical to cell motility. While these studies have implicated PECAM‐1‐dependent signaling in PECAM‐1‐mediated cell motility, the involvement of PECAM‐1 ligand binding in cell migration is undefined. Therefore to investigate the role of PECAM‐1 binding interactions in cell motility, mutants of PECAM‐1 were generated in which either homophilic or heparin/glycosaminoglycan (GAG)‐mediated heterophilic binding had been disabled and then expressed in an endothelial cell surrogate. We found that the ability of PECAM‐1 to stimulate cell migration, promote filopodia formation and trigger Cdc42 activation were lost if PECAM‐1‐dependent homophilic or heparin/GAG‐dependent heterophilic ligand binding was disabled. We further observed that PECAM‐1 concentrated at the tips of extended filopodia, an activity that was diminished if homophilic, but not heparin/GAG‐mediated heterophilic binding had been disrupted. Similar patterns of activities were seen in mouse endothelial cells treated with antibodies that specifically block PECAM‐1‐dependent homophilic or heterophilic adhesion. Together these data provide evidence for the differential involvement of PECAM‐1‐ligand interactions in PECAM‐1‐dependent motility and the extension of filopodia.

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“…2009), a Rho GTPase closely associated with the elaboration of these cellular extensions (Install and Machesky 2009; Ridley 2011). Consistent with previous published data (Cao et al.…”

Section: Resultsmentioning

confidence: 99%

“…Composed of tight parallel bundles of polymerized actin, these finger‐like projections contain adhesion molecules that are able to bind to the extracellular matrix and/or initiate intercellular signaling (Install and Machesky 2009; Bornschlog 2013; Blanchoin et al. 2014).…”

Section: Discussionmentioning

confidence: 99%

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

et al. 2016

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“…Although filamentous actin and several regulators of actin polymerization that mediate cell shape changes 39 have remained elusive in malaria blood stages 40 , the morphology changes of ring stages resembling filopodia like extensions are an indication of a functional and regulated cytoskeleton. To test a possible role of actin in these shape changes, we counted the number of round and amoeboid forms when parasites were grown for 1 h in the presence of the F actin stabilizer jasplakinolide.…”

Section: Resultsmentioning

confidence: 99%

Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions

et al. 2011

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Blood stages of Plasmodium falciparum cause the pathology of malaria; however, the progression of the parasite through this complex part of the life cycle has never been visualized. In this study, we use four-dimensional imaging to show for the first time the development of individual parasites in erythrocytes and the concomitant host cell modifications. our data visualize an unexpectedly dynamic parasite, provide a reference for this life cycle stage and challenge the model that protein export in P. falciparum is linked to the biogenesis of host cell modifications termed maurer's clefts. our results provide a novel view of the blood-stage development, maurer's cleft development and protein export in malaria parasites, and open the door to study dynamic processes, drug effects and the phenotype of mutants.

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“…Moreover, upon myosin inhibition, spreading fibroblasts acquire a C-like shape, with a convex edge that protrudes and stretches the membrane, and a concave edge that is retracted by the tension generated in the membrane (33), similar to what we observe in motile fragments. Additional modules, most prominently adhesion-and signaling-related, are known to play important roles in more complex cells (34). Adhesion is obviously essential for lamellipodial motility.…”

Section: Discussionmentioning

confidence: 99%

Actin disassembly clock determines shape and speed of lamellipodial fragments

Ofer

Mogilner

Keren

2011

Proc. Natl. Acad. Sci. U.S.A.

113

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A central challenge in motility research is to quantitatively understand how numerous molecular building blocks self-organize to achieve coherent shape and movement on cellular scales. A classic example of such self-organization is lamellipodial motility in which forward translocation is driven by a treadmilling actin network. Actin polymerization has been shown to be mechanically restrained by membrane tension in the lamellipodium. However, it remains unclear how membrane tension is determined, what is responsible for retraction and shaping of the rear boundary, and overall how actin-driven protrusion at the front is coordinated with retraction at the rear. To answer these questions, we utilize lamellipodial fragments from fish epithelial keratocytes which lack a cell body but retain the ability to crawl. The absence of the voluminous cell body in fragments simplifies the relation between lamellipodial geometry and cytoskeletal dynamics. We find that shape and speed are highly correlated over time within individual fragments, whereby faster crawling is accompanied by larger front-to-rear lamellipodial length. Furthermore, we find that the actin network density decays exponentially from front-to-rear indicating a constant net disassembly rate. These findings lead us to a simple hypothesis of a disassembly clock mechanism in which rear position is determined by where the actin network has disassembled enough for membrane tension to crush it and haul it forward. This model allows us to directly relate membrane tension with actin assembly and disassembly dynamics and elucidate the role of the cell membrane as a global mechanical regulator which coordinates protrusion and retraction.cell motility | keratocyte fragments U nderstanding the large-scale coordination of molecular processes into coherent behavior at the cellular level is one of the central challenges in cell biology. Actin-based motility involves numerous molecular players with complex interactions (1) that span a wide-range of scales from the molecular level to the cellular one. Despite substantial progress in characterizing the molecular details involved (2), we still do not understand the remarkable self-organization of these molecular components into a moving cell. The complex interplay between biochemical reactions and biophysical forces plays a central role in this selforganization. In particular, the mechanical feedback between the cell membrane and the dynamic actin network has been shown to have a substantial effect on cell protrusion (3, 4), and a significant role in coordinating protrusion over cellular scales (5, 6). However, quantitative understanding of the coupling between the cell membrane and the motility machinery is still lacking; it is unknown what determines membrane tension and how membrane tension is related to the protrusion and retraction dynamics. Elucidating this dynamic interplay is essential for understanding how overall cell morphology and movement emerge from the underlying molecular processes.Fish epithelial keratocytes are...

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Actin Dynamics at the Leading Edge: From Simple Machinery to Complex Networks

Cited by 378 publications

References 123 publications

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

Influence of PECAM-1 ligand interactions on PECAM-1-dependent cell motility and filopodia extension

Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions

Actin disassembly clock determines shape and speed of lamellipodial fragments

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