scholarly journals The Arp2/3 Regulatory System and Its Deregulation in Cancer

2018 ◽  
Vol 98 (1) ◽  
pp. 215-238 ◽  
Author(s):  
Nicolas Molinie ◽  
Alexis Gautreau
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Actin Filaments ◽  
Patient Survival ◽  
Regulatory System ◽  
Direct Impact ◽  
Actin Network ◽  
Actin Networks ◽  
Cross Links ◽  
The Stability

The Arp2/3 complex is an evolutionary conserved molecular machine that generates branched actin networks. When activated, the Arp2/3 complex contributes the actin branched junction and thus cross-links the polymerizing actin filaments in a network that exerts a pushing force. The different activators initiate branched actin networks at the cytosolic surface of different cellular membranes to promote their protrusion, movement, or scission in cell migration and membrane traffic. Here we review the structure, function, and regulation of all the direct regulators of the Arp2/3 complex that induce or inhibit the initiation of a branched actin network and that controls the stability of its branched junctions. Our goal is to present recent findings concerning novel inhibitory proteins or the regulation of the actin branched junction and place these in the context of what was previously known to provide a global overview of how the Arp2/3 complex is regulated in human cells. We focus on the human set of Arp2/3 regulators to compare normal Arp2/3 regulation in untransformed cells to the deregulation of the Arp2/3 system observed in patients affected by various cancers. In many cases, these deregulations promote cancer progression and have a direct impact on patient survival.

scholarly journals Efficiency of lamellipodia protrusion is determined by the extent of cytosolic actin assembly

2017 ◽  
Vol 28 (10) ◽  
pp. 1311-1325 ◽  
Author(s):  
Georgi Dimchev ◽  
Anika Steffen ◽  
Frieda Kage ◽  
Vanessa Dimchev ◽  
Julien Pernier ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Surface ◽  
Actin Filaments ◽  
Family Members ◽  
Cell Communication ◽  
Actin Assembly ◽  
Actin Monomer ◽  
Actin Network ◽  
Site Specific ◽  
Actin Networks

Cell migration and cell–cell communication involve the protrusion of actin-rich cell surface projections such as lamellipodia and filopodia. Lamellipodia are networks of actin filaments generated and turned over by filament branching through the Arp2/3 complex. Inhibition of branching is commonly agreed to eliminate formation and maintenance of lamellipodial actin networks, but the regulation of nucleation or elongation of Arp2/3-independent filament populations within the network by, for example, formins or Ena/VASP family members and its influence on the effectiveness of protrusion have been unclear. Here we analyzed the effects of a set of distinct formin fragments and VASP on site-specific, lamellipodial versus cytosolic actin assembly and resulting consequences on protrusion. Surprisingly, expression of formin variants but not VASP reduced lamellipodial protrusion in B16-F1 cells, albeit to variable extents. The rates of actin network polymerization followed a similar trend. Unexpectedly, the degree of inhibition of both parameters depended on the extent of cytosolic but not lamellipodial actin assembly. Indeed, excess cytosolic actin assembly prevented actin monomer from rapid translocation to and efficient incorporation into lamellipodia. Thus, as opposed to sole regulation by actin polymerases operating at their tips, the protrusion efficiency of lamellipodia is determined by a finely tuned balance between lamellipodial and cytosolic actin assembly.

scholarly journals N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ri-Xin Chen ◽  
Xin Chen ◽  
Liang-Ping Xia ◽  
Jia-Xing Zhang ◽  
Zhi-Zhong Pan ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Cancer Progression ◽  
Patient Survival ◽  
Circular Rnas ◽  
Serum Samples ◽  
Tumor Tissues ◽  
Metastasis Models ◽  
The Stability

Abstract Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

scholarly journals Synergy between Cyclase-associated protein and Cofilin accelerates actin filament depolymerization by two orders of magnitude

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shashank Shekhar ◽  
Johnson Chung ◽  
Jane Kondev ◽  
Jeff Gelles ◽  
Bruce L. Goode
Keyword(s):  
Actin Filament ◽  
Single Molecule ◽  
Actin Filaments ◽  
Binding Protein ◽  
Actin Dynamics ◽  
Actin Network ◽  
Cellular Mechanisms ◽  
Actin Networks ◽  
Binding Event

AbstractCellular actin networks can be rapidly disassembled and remodeled in a few seconds, yet in vitro actin filaments depolymerize slowly over minutes. The cellular mechanisms enabling actin to depolymerize this fast have so far remained obscure. Using microfluidics-assisted TIRF, we show that Cyclase-associated protein (CAP) and Cofilin synergize to processively depolymerize actin filament pointed ends at a rate 330-fold faster than spontaneous depolymerization. Single molecule imaging further reveals that hexameric CAP molecules interact with the pointed ends of Cofilin-decorated filaments for several seconds at a time, removing approximately 100 actin subunits per binding event. These findings establish a paradigm, in which a filament end-binding protein and a side-binding protein work in concert to control actin dynamics, and help explain how rapid actin network depolymerization is achieved in cells.

scholarly journals A barbed end interference mechanism reveals how capping protein promotes nucleation in branched actin networks

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Johanna Funk ◽  
Felipe Merino ◽  
Matthias Schaks ◽  
Klemens Rottner ◽  
Stefan Raunser ◽  
...  
Keyword(s):  
Structural Biology ◽  
Actin Filaments ◽  
Actin Network ◽  
Essential Factor ◽  
Actin Networks ◽  
Capping Protein ◽  
Cellular Processes ◽  
In Vitro Reconstitution ◽  
Interference Mechanism

AbstractHeterodimeric capping protein (CP/CapZ) is an essential factor for the assembly of branched actin networks, which push against cellular membranes to drive a large variety of cellular processes. Aside from terminating filament growth, CP potentiates the nucleation of actin filaments by the Arp2/3 complex in branched actin networks through an unclear mechanism. Here, we combine structural biology with in vitro reconstitution to demonstrate that CP not only terminates filament elongation, but indirectly stimulates the activity of Arp2/3 activating nucleation promoting factors (NPFs) by preventing their association to filament barbed ends. Key to this function is one of CP’s C-terminal “tentacle” extensions, which sterically masks the main interaction site of the terminal actin protomer. Deletion of the β tentacle only modestly impairs capping. However, in the context of a growing branched actin network, its removal potently inhibits nucleation promoting factors by tethering them to capped filament ends. End tethering of NPFs prevents their loading with actin monomers required for activation of the Arp2/3 complex and thus strongly inhibits branched network assembly both in cells and reconstituted motility assays. Our results mechanistically explain how CP couples two opposed processes—capping and nucleation—in branched actin network assembly.

Regulation of Actin Assembly Associated With Protrusion and Adhesion in Cell Migration

2008 ◽  
Vol 88 (2) ◽  
pp. 489-513 ◽  
Author(s):  
Christophe Le Clainche ◽  
Marie-France Carlier
Keyword(s):  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Actin Filaments ◽  
Actin Assembly ◽  
Concerted Action ◽  
Actin Networks ◽  
Capping Proteins ◽  
Cell Matrix ◽  
A Cell ◽  
Actomyosin Contraction

To migrate, a cell first extends protrusions such as lamellipodia and filopodia, forms adhesions, and finally retracts its tail. The actin cytoskeleton plays a major role in this process. The first part of this review (sect. ii) describes the formation of the lamellipodial and filopodial actin networks. In lamellipodia, the WASP-Arp2/3 pathways generate a branched filament array. This polarized dendritic actin array is maintained in rapid treadmilling by the concerted action of ADF, profilin, and capping proteins. In filopodia, formins catalyze the processive assembly of nonbranched actin filaments. Cell matrix adhesions mechanically couple actin filaments to the substrate to convert the treadmilling into protrusion and the actomyosin contraction into traction of the cell body and retraction of the tail. The second part of this review (sect. iii) focuses on the function and the regulation of major proteins (vinculin, talin, tensin, and α-actinin) that control the nucleation, the binding, and the barbed-end growth of actin filaments in adhesions.

scholarly journals Synergy between Wsp1 and Dip1 may initiate assembly of endocytic actin networks

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Connor J Balzer ◽  
Michael L James ◽  
Heidy Y Narvaez-Ortiz ◽  
Luke A Helgeson ◽  
Vladimir Sirotkin ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Schizosaccharomyces Pombe ◽  
Actin Filament ◽  
Single Molecule ◽  
Actin Filaments ◽  
Total Internal Reflection ◽  
Actin Assembly ◽  
Actin Network ◽  
Actin Networks ◽  
Co Activation

The actin filament nucleator Arp2/3 complex is activated at cortical sites in Schizosaccharomyces pombe to assemble branched actin networks that drive endocytosis. Arp2/3 complex activators Wsp1 and Dip1 are required for proper actin assembly at endocytic sites, but how they coordinately control Arp2/3-mediated actin assembly is unknown. Alone, Dip1 activates Arp2/3 complex without preexisting actin filaments to nucleate ‘seed’ filaments that activate Wsp1-bound Arp2/3 complex, thereby initiating branched actin network assembly. In contrast, because Wsp1 requires preexisting filaments to activate, it has been assumed to function exclusively in propagating actin networks by stimulating branching from preexisting filaments. Here we show that Wsp1 is important not only for propagation but also for initiation of endocytic actin networks. Using single molecule total internal reflection fluorescence microscopy we show that Wsp1 synergizes with Dip1 to co-activate Arp2/3 complex. Synergistic co-activation does not require preexisting actin filaments, explaining how Wsp1 contributes to actin network initiation in cells.

scholarly journals ARHGAP11A Promotes the Malignant Progression of Gastric Cancer by Regulating the Stability of Actin Filaments through TPM1

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xiaoying Guan ◽  
Xiaoli Guan ◽  
Junjie Qin ◽  
Long Qin ◽  
Wengui Shi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Actin Filaments ◽  
Poor Prognosis ◽  
Malignant Progression ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Cell Migration And Invasion ◽  
The Stability

The mechanism underlying the poor prognosis of gastric cancer, including its high degree of malignancy, invasion, and metastasis, is extremely complicated. Rho GTPases are involved in the occurrence and development of a variety of malignant tumors. ARHGAP11A, in the Rho GTPase activating protein family, is highly expressed in gastric cancer, but its function and mechanism have not yet been explored. In this study, the effect of ARHGAP11A on the occurrence and development of gastric cancer and the mechanism related to this effect were studied. The expression of ARHGAP11A was increased in gastric cancer cells and tissues, and high ARHGAP11A expression in tissues was related to the degree of tumor differentiation and poor prognosis. Moreover, ARHGAP11A knockout significantly inhibited cell proliferation, cell migration, and invasion in vitro and significantly inhibited the tumorigenic ability of gastric cancer cells in nude mice in vivo. Further studies revealed that ARHGAP11A promotes the malignant progression of gastric cancer cells by interacting with TPM1 to affect cell migration and invasion and the stability of actin filaments. These results suggest that ARHGAP11A plays an important role in gastric cancer and may become a useful prognostic biomarker and therapeutic target for gastric cancer patients.

Reptation of Microtubules in F-Actin Networks : Effects of Filament Stiffness and Network Topology on Reptation Dynamics

1997 ◽  
Vol 489 ◽  
Author(s):  
Jagesh V. Shah ◽  
Lisa A. Flanagan ◽  
David Bahk ◽  
Paul A. Janmey
Keyword(s):  
Network Topology ◽  
Actin Filaments ◽  
Diffusion Constant ◽  
Actin Network ◽  
Filamentous Actin ◽  
Actin Networks ◽  
Apparent Diffusion ◽  
Thermally Driven

AbstractThe thermally driven motions of fluorescently labeled microtubules embedded in a network of filamentous actin polymers are analysed as the diffusion of a rod-like polymer within a virtual tube formed by the surrounding semiflexible actin filaments. The apparent diffusion constant parallel to the tube scales with the inverse of the microtubule length and the magnitude is consistant with diffusion through a medium with a viscosity of approximately 10 centipoise. Introduction of crosslinks between the actin filaments does not alter the diffusion of the microtubules in the actin network.

The structure of cortical cytoplasm

1982 ◽  
Vol 299 (1095) ◽  
pp. 275-289 ◽  
Keyword(s):  
Actin Filaments ◽  
Cell Shape ◽  
Three Dimensional ◽  
The Other ◽  
Filament Length ◽  
Actin Network ◽  
Dimensional Lattice ◽  
High Affinity ◽  
Cross Links ◽  
Contractile Forces

Actin-rich cortical cytoplasm of phagocytic leucocytes forms pseudopodia and controls cell shape and movement by generating directional propulsive and contractile forces. Proteins purified from leucocytes form and deform an actin matrix. Actinbinding protein (ABP) cross-links actin filaments into a three-dimensional lattice with perpendicular branches. This structure, which can be visualized in the electron microscope, is consistent with physical properties of actin-ABP matrices. Gelsolin binds one end of actin filaments with high affinity in the presence of calcium; acumentin, another protein, constitutively binds the other end with low affinity. Together these proteins can control actin filament length and thereby regulate expansion (propulsion) or collapse of the actin network. The assembly state of the network also controls myosin-based contractile forces. A tug-of-war decides the direction of lattice movement, regions of lesser structure tending to move toward regions of greater structure.

scholarly journals Synergy between Wsp1 and Dip1 may initiate assembly of endocytic actin networks

2020 ◽  
Author(s):  
Connor J. Balzer ◽  
Michael L. James ◽  
Luke A. Helgeson ◽  
Vladimir Sirotkin ◽  
Brad J. Nolen
Keyword(s):  
Actin Filament ◽  
Single Molecule ◽  
Actin Filaments ◽  
Actin Assembly ◽  
Actin Network ◽  
Tirf Microscopy ◽  
Actin Networks ◽  
In Cells

AbstractThe actin filament nucleator Arp2/3 complex is activated at cortical sites in S. pombe to assemble branched actin networks that drive endocytosis. Arp2/3 complex activators Wsp1 and Dip1 are required for proper actin assembly at endocytic sites, but how they coordinately control Arp2/3-mediated actin assembly is unknown. Alone, Dip1 activates Arp2/3 complex without preexisting actin filaments to nucleate “seed” filaments that activate Wsp1-bound Arp2/3 complex, thereby initiating branched actin network assembly. In contrast, because Wsp1 requires pre-existing filaments to activate, it has been assumed to function exclusively in propagating actin networks by stimulating branching from pre-existing filaments. Here we show that Wsp1 is important not only for propagation, but also for initiation of endocytic actin networks. Using single molecule TIRF microscopy we show that Wsp1 synergizes with Dip1 to co-activate Arp2/3 complex. Synergistic coactivation does not require pre-existing actin filaments, explaining how Wsp1 contributes to actin network initiation in cells.

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