Antagonism between Ena/VASP Proteins and Actin Filament Capping Regulates Fibroblast Motility
TL;DR: It is concluded that Ena/VASP regulates cell motility by controlling the geometry of actin filament networks within lamellipodia.
About: This article is published in Cell.The article was published on 2002-05-17 and is currently open access. It has received 850 citations till now. The article focuses on the topics: Ena/Vasp homology proteins & Filopodia.
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TL;DR: A core set of proteins including actin, Arp2/3 complex, profilin, capping protein, and ADF/cofilin can reconstitute the process in vitro, and mathematical models of the constituent reactions predict the rate of motion.
3,793 citations
TL;DR: The increased understanding of the functions of various actin-associated proteins during the initiation and elongation of filopodia has provided new information on the mechanisms of filipodia formation in distinct cell types.
Abstract: Filopodia are thin, actin-rich plasma-membrane protrusions that function as antennae for cells to probe their environment. Consequently, filopodia have an important role in cell migration, neurite outgrowth and wound healing and serve as precursors for dendritic spines in neurons. The initiation and elongation of filopodia depend on the precisely regulated polymerization, convergence and crosslinking of actin filaments. The increased understanding of the functions of various actin-associated proteins during the initiation and elongation of filopodia has provided new information on the mechanisms of filopodia formation in distinct cell types.
1,601 citations
Cites background from "Antagonism between Ena/VASP Protein..."
...Initial analyses suggested that ENA/VASP proteins promote filopodia formation by preventing capping of actin filament barbed end...
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TL;DR: The sequencing of complete genomes provides a list that includes the proteins responsible for cellular regulation, but this does not immediately reveal what these proteins do, nor how they are assembled into the molecular machines and functional networks that control cellular behavior.
Abstract: The sequencing of complete genomes provides a list that includes the proteins responsible for cellular regulation. However, this does not immediately reveal what these proteins do, nor how they are assembled into the molecular machines and functional networks that control cellular behavior. The regulation of many different cellular processes requires the use of protein interaction domains to direct the association of polypeptides with one another and with phospholipids, small molecules, or nucleic acids. The modular nature of these domains, and the flexibility of their binding properties, have likely facilitated the evolution of cellular pathways. Conversely, aberrant interactions can induce abnormal cellular behavior and disease. The fundamental properties of protein interaction domains are discussed in this review and in detailed reviews on individual domains at Science's STKE at http://www.sciencemag.org/cgi/content/full/300/5618/445/DC1.
1,489 citations
TL;DR: This work has shown that a relatively small number of guidance factors can be used to generate intricate patterns of neuronal wiring through signaling pathways still only poorly understood.
Abstract: Axons are guided along specific pathways by attractive and repulsive cues in the extracellular environment. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules, including netrins, Slits, semaphorins, and ephrins. Guidance cues steer axons by regulating cytoskeletal dynamics in the growth cone through signaling pathways that are still only poorly understood. Elaborate regulatory mechanisms ensure that a given cue elicits the right response from the right axons at the right time but is otherwise ignored. With such regulatory mechanisms in place, a relatively small number of guidance factors can be used to generate intricate patterns of neuronal wiring.
1,335 citations
TL;DR: The feedback loop between biochemical and mechanical properties of actin organization at the molecular level in vitro is described and this knowledge is integrated into the current understanding of cellular actin organizations and its physiological roles.
Abstract: Tight coupling between biochemical and mechanical properties of the actin cytoskeleton drives a large range of cellular processes including polarity establishment, morphogenesis, and motility. This is possible because actin filaments are semi-flexible polymers that, in conjunction with the molecular motor myosin, can act as biological active springs or "dashpots" (in laymen's terms, shock absorbers or fluidizers) able to exert or resist against force in a cellular environment. To modulate their mechanical properties, actin filaments can organize into a variety of architectures generating a diversity of cellular organizations including branched or crosslinked networks in the lamellipodium, parallel bundles in filopodia, and antiparallel structures in contractile fibers. In this review we describe the feedback loop between biochemical and mechanical properties of actin organization at the molecular level in vitro, then we integrate this knowledge into our current understanding of cellular actin organization and its physiological roles.
1,128 citations
References
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TL;DR: Actin purified by a new, simple, and rapid purification procedure activated the ATPase activity of both heavy meromyosin and Subfragment 1 of heavy mercyosin, and this activation was not inhibited by the removal of Ca2+.
4,306 citations
"Antagonism between Ena/VASP Protein..." refers methods in this paper
...Actin was purified from chicken work; and (3) filaments that extended beyond the field of view were pectoral muscle as described (Spudich and Watt, 1971)....
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TL;DR: The authors are grateful for financial support from the National Institutes of Health (grants GM23244 and GM53905), and to very helpful comments on the manuscript from Elliot Elson, Vlodya Gelfand, Paul Matsudaira, Julie Theriot, and Sally Zigmond.
3,973 citations
TL;DR: A review briefly summarizes older studies and concentrates on recent studies on the mechanisms of action of cytochalasin and phalloidin.
Abstract: C YTOCHALASINS and phalloidins are two groups of small, naturally occurring organic molecules that bind to actin and alter its polymerization. They have been widely used to study the role of actin in biological processes and as models for actin-binding proteins. Functionally, cytochalasins resemble capping proteins, which block an end of actin filaments, nucleate polymerization, and shorten filaments. No known actin-binding protein stabilizes actin filaments as phalloidin does, but such proteins may have been missed. Cytochalasin and phalloidin have also helped to elucidate fundamental aspects of actin polymerization. This review briefly summarizes older studies and concentrates on recent v~rk on the mechanisms of action of cytochalasin and phalloidin.
1,978 citations
TL;DR: How motile cells regulate actin filament assembly at their leading edge is reviewed, including how Arp2/3 complex is incorporated into the network, and new filaments are capped rapidly, so that activated Arp1/2 complex must be supplied continuously to keep the network growing.
Abstract: We review how motile cells regulate actin filament assembly at their leading edge. Activation of cell surface receptors generates signals (including activated Rho family GTPases) that converge on integrating proteins of the WASp family (WASp, N-WASP, and Scar/WAVE). WASP family proteins stimulate Arp2/3 complex to nucleate actin filaments, which grow at a fixed 70 degrees angle from the side of pre-existing actin filaments. These filaments push the membrane forward as they grow at their barbed ends. Arp2/3 complex is incorporated into the network, and new filaments are capped rapidly, so that activated Arp2/3 complex must be supplied continuously to keep the network growing. Hydrolysis of ATP bound to polymerized actin followed by phosphate dissociation marks older filaments for depolymerization by ADF/cofilins. Profilin catalyzes exchange of ADP for ATP, recycling actin back to a pool of unpolymerized monomers bound to profilin and thymosin-beta 4 that is poised for rapid elongation of new barbed ends.
1,516 citations
TL;DR: It is shown that the thermal motions of the polymerizing filaments can produce a directed force, and this "elastic Brownian ratchet" can explain quantitatively the propulsion of Listeria and the protrusive mechanics of lamellipodia.
928 citations