Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process

Henson, Joan M.; Yeterian, Mesrob; Weeks, Richard; Medrano, Angela E.; Brown, Briana L.; Geist, Heather L.; Pais, Mollyann D.; Oldenbourg, Rudolf; Shuster, Charles B.

doi:10.1091/mbc.e14-07-1244

Cited by 72 publications

(62 citation statements)

References 47 publications

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“…For example, depletion or inactivation of Arp2/3 complex in fibroblasts results in the disappearance of lamellipodia and an increase in filopodia formation, likely by incorporation of the released pool of G-actin by formin or Ena/VASP (Figure 3 D) 7,12,47,48 . A similar Arp2/3 complex inactivation phenotype has also been reported in other cell types such as Drosophila S2, human osteosarcoma U2OS, rat adenocarcinoma MTLn3, Coelomocytes and Aplysia neuronal growth cones (Figure 3 E) 49–54 . Interestingly, in Aplysia neuronal growth cones, Arp2/3 complex inhibition does not increase the length of filopodia, but instead the rate of both filopodia elongation and retrograde flow are increased 54 .…”

Section: Introductionsupporting

confidence: 82%

Internetwork competition for monomers governs actin cytoskeleton organization

Suarez

Kovar

2016

Nat Rev Mol Cell Biol

158

133

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Cells precisely control the formation of dynamic actin cytoskeletal networks to coordinate fundamental processes including motility, division, endocytosis and polarization. To support these functions, actin filament networks must be assembled, maintained and disassembled at the correct time and place, and with proper filament organization and dynamics. Regulation of the extent of filament network assembly and their organization have been largely attributed to the coordinated activation of actin assembly factors through signalling cascades. Here we discuss an intriguing model in which actin monomer availability is limiting, and competition between homeostatic actin cytoskeletal networks for actin monomers is an additional crucial regulatory mechanism that influences density and size of different actin networks, thereby contributing to the organization of the cellular actin cytoskeleton.

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Section: Introductionsupporting

confidence: 82%

Internetwork competition for monomers governs actin cytoskeleton organization

Suarez

Kovar

2016

Nat Rev Mol Cell Biol

158

133

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“…Importantly, the strong localization of the Arp2/3 complex at the edge of control hiCMs was absent in CK666 treated hiCMs (Figures 2C and 2D). The delocalization of the Arp2/3 complex from the leading edge is consistent with inactivation by CK666, as shown previously in non-muscle cells (Henson et al, 2015).…”

Section: Formins But Not the Arp2/3 Complex Are Required For Msf-basesupporting

confidence: 89%

Muscle specific stress fibers give rise to sarcomeres and are mechanistically distinct from stress fibers in non-muscle cells

Taneja

et al. 2017

Preprint

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The sarcomere is the basic contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating thin (i.e., actin) and thick (i.e., myosin) filament assembly during sarcomere formation. Thus, we developed an assay using human cardiomyocytes to test de novo sarcomere assembly. Using this assay, we report a population of muscle-specific stress fibers are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from these muscle stress fibers. This process requires formin-mediated but not Arp2/3-mediated actin polymerization and nonmuscle myosin IIB but not non-muscle myosin IIA. Furthermore, we show a short species of β cardiac myosin II filaments grows to form ~1.5 long filaments that then "stitch" together to form the stack of filaments at the core of the sarcomere (i.e., A-band). Interestingly, these are different from mechanisms that have previously been reported during stress fiber assembly in non-muscle cells. Thus, we provide a new model of cardiac sarcomere assembly based on distinct mechanisms of stress fiber regulation between non-muscle and muscle cells.

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“…To examine the contributions of Cdc42 and the different actin nucleating factors in promoting filopodial formation, embryos were treated at the blastula stage with DMSO or inhibitors for the Arp2/3 complex (CK666) or formins (SMIFH2) (Fig. 7A), which have been shown to inhibit branched and linear actin networks in sea urchin coelomocytes (Henson et al, 2014, 2015). Whereas control embryos at the gastrula stage exhibited organized VLCs, filopodia and growing spicules (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To block Cdc42 activity, embryos were cultured in the presence of the Cdc42 small molecule inhibitor ML141 (Tocris). To block Arp2/3 and formin-mediated actin polymerization, embryos were cultured in the presence of CK666 and SMIFH2 (Tocris), respectively (Henson et al, 2014, 2015). DMSO alone (0.1%) was used as a carrier control for all pharmacological treatments.…”

Section: Methodsmentioning

confidence: 99%

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

Sepúlveda-Ramírez

Toledo-Jacobo

Henson

et al. 2018

Developmental Biology

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In the sea urchin embryo, gastrulation is characterized by the ingression and directed cell migration of primary mesenchyme cells (PMCs), as well as the primary invagination and convergent extension of the endomesoderm. Like all cell shape changes, individual and collective cell motility is orchestrated by Rho family GTPases and their modulation of the actomyosin cytoskeleton. And while endomesoderm specification has been intensively studied in echinoids, much less is known about the proximate regulators driving cell motility. Toward these ends, we employed anti-sense morpholinos, mutant alleles and pharmacological inhibitors to assess the role of Cdc42 during sea urchin gastrulation. While inhibition of Cdc42 expression or activity had only mild effects on PMC ingression, PMC migration, alignment and skeletogenesis were disrupted in the absence of Cdc42, as well as elongation of the archenteron. PMC migration and patterning of the larval skeleton relies on the extension of filopodia, and Cdc42 was required for filopodia in vivo as well as in cultured PMCs. Lastly, filopodial extension required both Arp2/3 and formin actin-nucleating factors, supporting models of filopodial nucleation observed in other systems. Together, these results suggest that Cdc42 plays essential roles during PMC cell motility and organogenesis.

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Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process

Cited by 72 publications

References 47 publications

Internetwork competition for monomers governs actin cytoskeleton organization

Internetwork competition for monomers governs actin cytoskeleton organization

Muscle specific stress fibers give rise to sarcomeres and are mechanistically distinct from stress fibers in non-muscle cells

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo

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