Antagonism between Ena/VASP Proteins and Actin Filament Capping Regulates Fibroblast Motility

Bear, James E.; Svitkina, Tatyana; Krause, Matthias; Schafer, Dorothy A.; Loureiro, Joseph; Strasser, Geraldine; Maly, Ivan V.; Chaga, Oleg Y.; Cooper, John A.; Borisy, Gary G.; Gertler, Frank B.

doi:10.1016/s0092-8674(02)00731-6

Cited by 762 publications

(839 citation statements)

References 37 publications

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“…In fibroblasts with sequestered mena, the actin is highly branched and consists of short filaments with barbed ends oriented towards the membrane. When mena is targeted to the cell membrane, though, the actin filaments are much longer, less branched, and have barbed ends with less uniform orientation, more like the actin meshwork observed in growth cones (Bear et al 2002). In fact, mena colocalizes with the actin bundles and filopodia of NG108 growth cones.…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 98%

“…Ena/VASP proteins appear to function by binding to the barbed ends of filaments and competing with capping protein, allowing for longer filament extension (Bear et al 2002). Whereas capping protein binds tightly to the barbed ends in the fibroblast model of dendritic nucleation, causing branches to be short, ena/VASP proteins could function to inhibit capping and allow longer filaments to form.…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

“…One mechanism is based on the observation that cells with sequestered mena show more stable lamellipodia, whereas cells with membrane-targeted mena exhibit more dynamic lamellipodia with increased ruffling. Lamellipodia that are more frequently extended and retracted may be less likely to contribute to a total forward translocation of the cell (Bear et al 2002). It is early to tell where ena/VASP proteins would fit into a signaling model, but there is some evidence to suggest they function downstream of rho GTPases.…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

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Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Meyer

Feldman

2002

Journal of Neurochemistry

170

108

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Actin-based motility is critical for nervous system development. Both the migration of neurons and the extension of neurites require organized actin polymerization to push the cell membrane forward. Numerous extracellular stimulants of motility and axon guidance cues regulate actin-based motility through the rho GTPases (rho, rac, and cdc42). The rho GTPases reorganize the actin cytoskeleton, leading to stress fiber, filopodium, or lamellipodium formation. The activity of the rho GTPases is regulated by a variety of proteins that either stimulate GTP uptake (activation) or hydrolysis (inactivation). These proteins potentially link extracellular signals to the activation state of rho GTPases. Effectors downstream of the rho GTPases that directly influence actin polymerization have been identified and are involved in neurite development.The Arp2/3 complex nucleates the formation of new actin branches that extend the membrane forward. Ena/VASP proteins can cause the formation of longer actin filaments, characteristic of growth cone actin morphology, by preventing the capping of barbed ends. Actin-depolymerizing factor (ADF)/cofilin depolymerizes and severs actin branches in older parts of the actin meshwork, freeing monomers to be re-incorporated into actively growing filaments. The signaling mechanisms by which extracellular cues that guide axons to their targets lead to direct effects on actin filament dynamics are becoming better understood. Keywords: actin-depolymerizing factor (ADF)/cofilin, actinrelated protein Arp2/3, ena/VASP, LIM kinase, rho GTPase.

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Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 98%

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

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Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Meyer

Feldman

2002

Journal of Neurochemistry

170

108

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“…Hence, we determined whether regulation of linear actin polymerization could be targeted to decrease ex vivo aortic stiffness. The N‐terminal EVH1 domain of ena‐VASP family members localizes VASP to zyxin in vascular FAs, facilitating linear actin polymerization at those sites 41, 42. Because of the length of the EVH1 domain, we synthesized the analogous decoy construct by making EVH1 domain, attached to the TAT cell permeation tag, as a recombinant protein.…”

Section: Resultsmentioning

confidence: 99%

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

Nicholson

Singh

Saphirstein

et al. 2018

JAHA

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BackgroundThe proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.Methods and ResultsWe examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome‐wide association study of carotid‐femoral pulse wave velocity. Common genetic variation in the N‐WASP (WASL) locus is associated with carotid‐femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N‐WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N‐WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin‐vinculin interfaces similarly decreased aging‐induced ex vivo active stiffness by on‐target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound‐targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.ConclusionsWe conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein‐protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein‐protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

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“…Phalloidin staining showed centralised nuclei embedded in a diffuse network of actin microfilaments whereas peripheral nuclei were often linked to larger bundles of fibres. Phalloidin oleate, a cell permeable inhibitor of stable actin formation, and cytochalasin D which affects actin filament elongation (Bear et al, 2002) prevented nuclear aggregation and reduced the fusion index, suggesting that actin microfilament elongation enabled nuclear reorganisation in giant cells and has a role in cell fusion.…”

Section: Discussionmentioning

confidence: 99%

Enhanced formation of giant cells in common variable immunodeficiency: Relation to granulomatous disease

Scott-Taylor

Whiting

Pettengell

et al. 2017

Clinical Immunology

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Peripheral monocytes from patients with common variable immunodeficiency (CVID) had on average a 2 fold greater tendency to form giant cells in medium without additional cytokines. Giant cell formation was faster and 3 to 5 fold higher in most CVID cells compared to normal. Addition of IL4, GMCSF, IFNγ, TNFa and both T cell and monocyte conditioned media promoted monocyte fusion of some CVID individuals over 5 fold the normal average level, with combinations of cytokines and monokines acting synergistically. The reduction of normal giant cell formation by anti-IFNγ antibody and a greater tendency of CVID cells to fuse in immunoglobulin conditioned media suggests that standard IVIg treatment contributes to granuloma formation. CVID and normal giant cells expressed similar levels of phenotypic molecules and had similar phagocytic activity. Monocytes from many CVID patients have an elevated tendency to fuse which may explain the high incidence of granulomatous complications in CVID.

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Antagonism between Ena/VASP Proteins and Actin Filament Capping Regulates Fibroblast Motility

Cited by 762 publications

References 37 publications

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

Enhanced formation of giant cells in common variable immunodeficiency: Relation to granulomatous disease

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