Force Generation by Actin Polymerization II: The Elastic Ratchet and Tethered Filaments

Mogilner, Alex; Oster, George

doi:10.1016/s0006-3495(03)74969-8

Cited by 484 publications

(543 citation statements)

References 41 publications

(104 reference statements)

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“…These observations raised concerns that such tethers would prevent actin polymerization from moving the barriers, so Mogilner and Oster expanded the elastic Brownian ratchet model to take these tethers into account (14). In their revised model, Arp2/3 complex and newly formed filaments are linked briefly to the load, but they detach and generate force by the elastic Brownian ratchet mechanism until they are capped.…”

Section: Mogilner and Oster 2003mentioning

confidence: 99%

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Theory from the Oster Laboratory Leaps Ahead of Experiment in Understanding Actin-Based Cellular Motility

Pollard

2016

Biophysical Journal

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By the early 1990s, most biophysicists and cell biologists agreed that polymerization of actin filaments at the leading edge of a motile cell pushes the plasma membrane forward, creating a protrusion that extends the border of the cell (Fig. 1). For cells on a flat substrate, like a microscope slide, this leading edge is a relatively flat lamella less than 1 mm thick. To balance protrusion at the front end, contractility of the cytoplasm was believed to pull the rear of the cell forward toward attachments that form continuously behind the leading edge.Multiple lines of evidence supported the idea that actin polymerization drives cellular movements. Early electron micrographs of thin sections showed microfilaments (subsequently confirmed to be actin) in the cytoplasm next to the leading edge (1). Even better, electron micrographs of negatively stained specimens showed dense arrays of filaments at angles to the plasma membrane (2). Drugs that interfere with actin polymerization stop the protrusion of the leading edge (3), and two elegant fluorescence microscopy experiments established that actin polymerizes near the leading edge. First, Yu-Li Wang injected live cells with fluorescent actin, which incorporated into cellular actin structures (4). When he bleached a spot in the fluorescent leading lamella of the stationary cell, the spot moved away from the leading edge as new fluorescent actin was incorporated next to the plasma membrane. Over time, the fluorescence recovered, showing that the filaments turned over. Julie Theriot and Tim Mitchison used photoactivation to learn more (5). They injected motile cells with actin coupled to a ''caged'' fluorescent dye. After the tagged actin molecules incorporated into cellular actin structures, they uncaged the fluorescent dye with a light pulse near the leading edge. As the cell moved forward, the spot of fluorescent actin was stationary relative to the substrate and turned over on a time scale of tens of seconds. Electron microscopy (2) showed that these leading edge actin filaments are mostly oriented with their faster growing ''barbed ends'' (6) toward the leading edge of motile cells.Many of these ideas were reinforced by parallel experiments on the movements of certain bacteria through the cytoplasm of host animal cells (7). Actin polymerization next to the bacterium assembles a comet tail of actin filaments that propels the bacterium through the cytoplasm (8,9). This work culminated in reconstitution of bacterial motility from purified actin and a few other proteins (10).Knowing the equilibrium constant for subunit addition to actin filaments, Hill and Kirschner made solid thermodynamic arguments for how polymerization might produce the force to push the membrane forward (11). However, Peskin, Odell, and Oster (12) pointed out ''such arguments provide no mechanistic explanation of how the free energy of polymerization is actually transduced into directed mechanical force.'' A series of three classic papers in Biophysical Journal by George Oster with Charles Peskin...

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Section: Mogilner and Oster 2003mentioning

confidence: 99%

“…This paper also worked out the optimal geometrical conditions for such a Brownian ratchet to displace the barrier. The third paper (14) showed how the elastic Brownian ratchet works even if some of the actin filaments are transiently linked to the load. These papers were successful for two reasons.…”

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confidence: 99%

Theory from the Oster Laboratory Leaps Ahead of Experiment in Understanding Actin-Based Cellular Motility

Pollard

2016

Biophysical Journal

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“…This concept is illustrated by considering force generation by the actin cytoskeleton machinery, which is used for numerous processes within the cell including the process that drives membrane protrusion [61,62]. Force generation by the actin cytoskeleton can be studied at two levels.…”

Section: From Signaling Network To Functionsmentioning

confidence: 99%

“…At the chemical level, one needs to model the biochemical reactions that underlie the actin polymerization and depolymerization cycles, and the regulation of these reactions by the signaling network [63]. At a physical level, one needs to understand how the polymerization and depolymerization cycles of actin generate force, and conversely, how mechanical force modulates the kinetics of polymerization and depolymerization [61,62]. This interdependence between mechanics and chemistry determines whether polymerization occurs, and whether it can provide enough protrusive force to push the cell membrane forward.…”

Section: From Signaling Network To Functionsmentioning

confidence: 99%

“…It is important to note that models based on thermodynamic arguments provide only theoretical limits within which the system can operate, but do not provide mechanistic details. Elegant models that analyze the relationship between filament assembly and force generation have been proposed at both the single filament and at the `actin-gel' level [61,70]. Integration of these mechanochemical models of filament assembly and force generation with models of the signaling networks might enable prediction of how signals from the extracellular matrix can control the rate of cell movement.…”

Section: From Signaling Network To Functionsmentioning

confidence: 99%

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Computational approaches for modeling regulatory cellular networks

Eungdamrong

Iyengar

2004

Trends in Cell Biology

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Cellular components interact with each other to form networks that process information and evoke biological responses. A deep understanding of the behavior of these networks requires the development and analysis of mathematical models. In this article, different types of mathematical representations for modeling signaling networks are described, and the advantages and disadvantages of each type are discussed. Two experimentally well-studied signaling networks are then used as examples to illustrate the insight that could be gained through modeling. Finally, the modeling approach is expanded to describe how signaling networks might regulate cellular machines and evoke phenotypic behaviors.During the past two decades, substantial progress has been made in understanding the biochemical properties of cellular components, in addition to the organization of various molecular machines such as those involved in transcription and motility. From these studies of components and pathways, the design principles underlying cellular networks have emerged [1,2]. However, a substantial number of experiments is still needed to build up thè parts list' for a cell and to specify `parts function' in terms of cellular location, dynamics and regulatory organization. Because of the sheer number of components and interactions, the analysis of regulatory interactions is not easily achieved through intuition; even pathways and networks with few components are configured into systems that display complex behaviors. Hence, it is becoming increasingly clear that quantitative descriptions that lead to predictive models can be of great use in analyzing signaling pathways.Models of regulatory networks can be developed at various levels. Each level has its value. The simplest models of regulatory pathways and networks depict them as connections maps (http://stke.sciencemag.org), which are useful starting points for detailed analyses of signaling pathways. Although many signaling pathways have been identified by the study of binary reactions, connections are increasingly deduced from high-throughput experimental analyses of both protein-protein interactions [3][4][5][6] and protein location and expression patterns [7,8]. However, these connection maps are largely qualitative and, hence, only limited mathematical analysis can be undertaken. Such analyses often fall along the line of statistical correlations (`clustering'), which reveals co-regulation of each component [9], or an analysis of how the components are connected, which describes the statistical properties of the network as a whole [10][11][12]. An advantage of these models is that they can be developed for large numbers of components and interactions, and are useful in obtaining an To understand how extracellular signals evoke dynamic cellular responses, an analysis of the chemical reactions that constitute a biological system is needed. Typically, such models are built in three stages. First, a biochemical scheme that depicts the chemical reactions between the components in the...

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Molecular mechanisms of force production in clathrin‐mediated endocytosis

et al. 2018

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During clathrin-mediated endocytosis (CME), a flat patch of membrane is invaginated and pinched off to release a vesicle into the cytoplasm. In yeast CME, over 60 proteins—including a dynamic actin meshwork—self-assemble to deform the plasma membrane. Several models have been proposed for how actin and other molecules produce the forces necessary to overcome the mechanical barriers of membrane tension and turgor pressure, but the precise mechanisms and a full picture of their interplay are still not clear. In this review, we discuss the evidence for these force production models from a quantitative perspective and propose future directions for experimental and theoretical work that could clarify their various contributions.

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Force Generation by Actin Polymerization II: The Elastic Ratchet and Tethered Filaments

Cited by 484 publications

References 41 publications

Theory from the Oster Laboratory Leaps Ahead of Experiment in Understanding Actin-Based Cellular Motility

Theory from the Oster Laboratory Leaps Ahead of Experiment in Understanding Actin-Based Cellular Motility

Computational approaches for modeling regulatory cellular networks

Molecular mechanisms of force production in clathrin‐mediated endocytosis

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