Journal articles: 'Actin regulators'

1

Ma, Xuda, Yamei Dang, Xiaowen Shao, Xuechun Chen, Fei Wu, and Yongmei Li. "Ubiquitination and Long Non-coding RNAs Regulate Actin Cytoskeleton Regulators in Cancer Progression." International Journal of Molecular Sciences 20, no. 12 (June 19, 2019): 2997. http://dx.doi.org/10.3390/ijms20122997.

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Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs (LIM domain kinases), and SSH1 (slingshot family protein phosphate 1). Ubiquitination, as a ubiquitous post-transcriptional modification, deceases protein levels of actin cytoskeleton regulatory factors and thereby modulates the actin cytoskeleton. There is increasing evidence showing cytoskeleton regulation by long noncoding RNAs (lncRNAs) in cancer metastasis. However, which E3 ligases are activated for the ubiquitination of actin-cytoskeleton regulators involved in tumor metastasis remains to be fully elucidated. Moreover, it is not clear how lncRNAs influence the expression of actin cytoskeleton regulators. Here, we summarize physiological and pathological mechanisms of lncRNAs and ubiquitination control mediators of actin cytoskeleton regulators which that are involved in tumorigenesis and tumor progression. Finally, we briefly discuss crosstalk between ubiquitination and lncRNA control mediators of actin-cytoskeleton regulators in cancer.

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Siripala, Anosha D., and Matthew D. Welch. "SnapShot: Actin Regulators I." Cell 128, no. 3 (February 2007): 626.e1–626.e2. http://dx.doi.org/10.1016/j.cell.2007.02.001.

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Siripala, Anosha D., and Matthew D. Welch. "SnapShot: Actin Regulators II." Cell 128, no. 5 (March 2007): 1014.e1–1014.e2. http://dx.doi.org/10.1016/j.cell.2007.02.021.

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Ferrai, Carmelo, Gabriela Naum-Onganía, Elena Longobardi, Martina Palazzolo, Andrea Disanza, Victor M. Diaz, Massimo P. Crippa, Giorgio Scita, and Francesco Blasi. "Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization." Molecular Biology of the Cell 20, no. 15 (August 2009): 3543–51. http://dx.doi.org/10.1091/mbc.e09-02-0114.

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We have analyzed the role of actin polymerization in retinoic acid (RA)-induced HoxB transcription, which is mediated by the HoxB regulator Prep1. RA induction of the HoxB genes can be prevented by the inhibition of actin polymerization. Importantly, inhibition of actin polymerization specifically affects the transcription of inducible Hox genes, but not that of their transcriptional regulators, the RARs, nor of constitutively expressed, nor of actively transcribed Hox genes. RA treatment induces the recruitment to the HoxB2 gene enhancer of a complex composed of “elongating” RNAPII, Prep1, β-actin, and N-WASP as well as the accessory splicing components p54Nrb and PSF. We show that inhibition of actin polymerization prevents such recruitment. We conclude that inducible Hox genes are selectively sensitive to the inhibition of actin polymerization and that actin polymerization is required for the assembly of a transcription complex on the regulatory region of the Hox genes.

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Rohn, Jennifer L., David Sims, Tao Liu, Marina Fedorova, Frieder Schöck, Joseph Dopie, Maria K. Vartiainen, Amy A. Kiger, Norbert Perrimon, and Buzz Baum. "Comparative RNAi screening identifies a conserved core metazoan actinome by phenotype." Journal of Cell Biology 194, no. 5 (September 5, 2011): 789–805. http://dx.doi.org/10.1083/jcb.201103168.

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Although a large number of actin-binding proteins and their regulators have been identified through classical approaches, gaps in our knowledge remain. Here, we used genome-wide RNA interference as a systematic method to define metazoan actin regulators based on visual phenotype. Using comparative screens in cultured Drosophila and human cells, we generated phenotypic profiles for annotated actin regulators together with proteins bearing predicted actin-binding domains. These phenotypic clusters for the known metazoan “actinome” were used to identify putative new core actin regulators, together with a number of genes with conserved but poorly studied roles in the regulation of the actin cytoskeleton, several of which we studied in detail. This work suggests that although our search for new components of the core actin machinery is nearing saturation, regulation at the level of nuclear actin export, RNA splicing, ubiquitination, and other upstream processes remains an important but unexplored frontier of actin biology.

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Martin, Jose L., Aaqil Khan, and Elena E. Grintsevich. "Actin Isoform Composition and Binding Factors Fine-Tune Regulatory Impact of Mical Enzymes." International Journal of Molecular Sciences 24, no. 23 (November 23, 2023): 16651. http://dx.doi.org/10.3390/ijms242316651.

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Mical family enzymes are unusual actin regulators that prime filaments (F-actin) for disassembly via the site-specific oxidation of M44/M47. Filamentous actin acts as a substrate of Mical enzymes, as well as an activator of their NADPH oxidase activity, which leads to hydrogen peroxide generation. Mical enzymes are required for cytokinesis, muscle and heart development, dendritic pruning, and axonal guidance, among other processes. Thus, it is critical to understand how this family of actin regulators functions in different cell types. Vertebrates express six actin isoforms in a cell-specific manner, but MICALs’ impact on their intrinsic properties has never been systematically investigated. Our data reveal the differences in the intrinsic dynamics of Mical-oxidized actin isoforms. Furthermore, our results connect the intrinsic dynamics of actin isoforms and their redox state with the patterns of hydrogen peroxide (H2O2) generation by MICALs. We documented that the differential properties of actin isoforms translate into the distinct patterns of hydrogen peroxide generation in Mical/NADPH-containing systems. Moreover, our results establish a conceptual link between actin stabilization by interacting factors and its ability to activate MICALs’ NADPH oxidase activity. Altogether, our results suggest that the regulatory impact of MICALs may differ depending on the isoform-related identities of local actin networks.

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Burston, Helen E., Lymarie Maldonado-Báez, Michael Davey, Benjamen Montpetit, Cayetana Schluter, Beverly Wendland, and Elizabeth Conibear. "Regulators of yeast endocytosis identified by systematic quantitative analysis." Journal of Cell Biology 185, no. 6 (June 8, 2009): 1097–110. http://dx.doi.org/10.1083/jcb.200811116.

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Endocytosis of receptors at the plasma membrane is controlled by a complex mechanism that includes clathrin, adaptors, and actin regulators. Many of these proteins are conserved in yeast yet lack observable mutant phenotypes, which suggests that yeast endocytosis may be subject to different regulatory mechanisms. Here, we have systematically defined genes required for internalization using a quantitative genome-wide screen that monitors localization of the yeast vesicle-associated membrane protein (VAMP)/synaptobrevin homologue Snc1. Genetic interaction mapping was used to place these genes into functional modules containing known and novel endocytic regulators, and cargo selectivity was evaluated by an array-based comparative analysis. We demonstrate that clathrin and the yeast AP180 clathrin adaptor proteins have a cargo-specific role in Snc1 internalization. We additionally identify low dye binding 17 (LDB17) as a novel conserved component of the endocytic machinery. Ldb17 is recruited to cortical actin patches before actin polymerization and regulates normal coat dynamics and actin assembly. Our findings highlight the conserved machinery and reveal novel mechanisms that underlie endocytic internalization.

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Steinestel, Konrad, Eva Wardelmann, Wolfgang Hartmann, and Inga Grünewald. "Regulators of Actin Dynamics in Gastrointestinal Tract Tumors." Gastroenterology Research and Practice 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/930157.

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Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells.

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Ono, Kanako, and Shoichiro Ono. "Tropomyosin and Troponin Are Required for Ovarian Contraction in the Caenorhabditis elegans Reproductive System." Molecular Biology of the Cell 15, no. 6 (June 2004): 2782–93. http://dx.doi.org/10.1091/mbc.e04-03-0179.

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Ovulation in the nematode Caenorhabditis elegans is coordinated by interactions between the somatic gonad and germ cells. Myoepithelial sheath cells of the proximal ovary are smooth muscle-like cells, but the regulatory mechanism of their contraction is unknown. We show that contraction of the ovarian muscle requires tropomyosin and troponin, which are generally major actin-linked regulators of contraction of striated muscle. RNA interference of tropomyosin or troponin C caused sterility by inhibiting ovarian contraction that is required for expelling mature oocytes into the spermatheca where fertilization takes place, thus causing accumulation of endomitotic oocytes in the ovary. Tropomyosin and troponin C were associated with actin filaments in the myoepithelial sheath, and the association of troponin C with actin was dependent on tropomyosin. A mutation in the actin depolymerizing factor/cofilin gene suppressed the ovulation defects by RNA interference of tropomyosin or troponin C. These results strongly suggest that tropomyosin and troponin are the actin-linked regulators for contraction of ovarian muscle in the C. elegans reproductive system.

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Zhang, Huaye, Donna J. Webb, Hannelore Asmussen, and Alan F. Horwitz. "Synapse formation is regulated by the signaling adaptor GIT1." Journal of Cell Biology 161, no. 1 (April 14, 2003): 131–42. http://dx.doi.org/10.1083/jcb.200211002.

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Dendritic spines in the central nervous system undergo rapid actin-based shape changes, making actin regulators potential modulators of spine morphology and synapse formation. Although several potential regulators and effectors for actin organization have been identified, the mechanisms by which these molecules assemble and localize are not understood. Here we show that the G protein–coupled receptor kinase–interacting protein (GIT)1 serves such a function by targeting actin regulators and locally modulating Rac activity at synapses. In cultured hippocampal neurons, GIT1 is enriched in both pre- and postsynaptic terminals and targeted to these sites by a novel domain. Disruption of the synaptic localization of GIT1 by a dominant-negative mutant results in numerous dendritic protrusions and a significant decrease in the number of synapses and normal mushroom-shaped spines. The phenotype results from mislocalized GIT1 and its binding partner PIX, an exchange factor for Rac. In addition, constitutively active Rac shows a phenotype similar to the GIT1 mutant, whereas dominant-negative Rac inhibits the dendritic protrusion formation induced by mislocalized GIT1. These results demonstrate a novel function for GIT1 as a key regulator of spine morphology and synapse formation and point to a potential mechanism by which mutations in Rho family signaling leads to decreased neuronal connectivity and cognitive defects in nonsyndromic mental retardation.

11

May, R. "Gene fishing: novel actin regulators netted." Trends in Cell Biology 8, no. 11 (November 1, 1998): 435. http://dx.doi.org/10.1016/s0962-8924(98)01399-3.

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12

Schlüter, Kathrin, Brigitte M. Jockusch, and Martin Rothkegel. "Profilins as regulators of actin dynamics." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1359, no. 2 (November 1997): 97–109. http://dx.doi.org/10.1016/s0167-4889(97)00100-6.

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Bernard, Ora. "Lim kinases, regulators of actin dynamics." International Journal of Biochemistry & Cell Biology 39, no. 6 (January 2007): 1071–76. http://dx.doi.org/10.1016/j.biocel.2006.11.011.

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Paredez, Alexander R., Arash Nayeri, Jennifer W. Xu, Jana Krtková, and W. Zacheus Cande. "Identification of Obscure yet Conserved Actin-Associated Proteins in Giardia lamblia." Eukaryotic Cell 13, no. 6 (April 11, 2014): 776–84. http://dx.doi.org/10.1128/ec.00041-14.

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ABSTRACTConsistent with its proposed status as an early branching eukaryote,Giardiahas the most divergent actin of any eukaryote and lacks core actin regulators. Although conserved actin-binding proteins are missing fromGiardia, its actin is utilized similarly to that of other eukaryotes and functions in core cellular processes such as cellular organization, endocytosis, and cytokinesis. We set out to identify actin-binding proteins inGiardiausing affinity purification coupled with mass spectroscopy (multidimensional protein identification technology [MudPIT]) and have identified >80 putative actin-binding proteins. Several of these have homology to conserved proteins known to complex with actin for functions in the nucleus and flagella. We validated localization and interaction for seven of these proteins, including 14-3-3, a known cytoskeletal regulator with a controversial relationship to actin. Our results indicate that althoughGiardialacks canonical actin-binding proteins, there is a conserved set of actin-interacting proteins that are evolutionarily indispensable and perhaps represent some of the earliest functions of the actin cytoskeleton.

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Sun, Shao-Chen, and Nam-Hyung Kim. "Molecular Mechanisms of Asymmetric Division in Oocytes." Microscopy and Microanalysis 19, no. 4 (June 14, 2013): 883–97. http://dx.doi.org/10.1017/s1431927613001566.

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AbstractIn contrast to symmetric division in mitosis, mammalian oocyte maturation is characterized by asymmetric cell division that produces a large egg and a small polar body. The asymmetry results from oocyte polarization, which includes spindle positioning, migration, and cortical reorganization, and this process is critical for fertilization and the retention of maternal components for early embryo development. Although actin dynamics are involved in this process, the molecular mechanism underlying this remained unclear until the use of confocal microscopy and live cell imaging became widespread in recent years. Information obtained through a PubMed database search of all articles published in English between 2000 and 2012 that included the phrases “oocyte, actin, spindle migration,” “oocyte, actin, polar body,” or “oocyte, actin, asymmetric division” was reviewed. The actin nucleation factor actin-related protein 2/3 complex and its nucleation-promoting factors, formins and Spire, and regulators such as small GTPases, partitioning-defective/protein kinase C, Fyn, microRNAs, cis-Golgi apparatus components, myosin/myosin light-chain kinase, spindle stability regulators, and spindle assembly checkpoint regulators, play critical roles in asymmetric cell division in oocytes. This review summarizes recent findings on these actin-related regulators in mammalian oocyte asymmetric division and outlines a complete signaling pathway.

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Gentile, Juliana E., Melissa G. Carrizales, and Anthony J. Koleske. "Control of Synapse Structure and Function by Actin and Its Regulators." Cells 11, no. 4 (February 9, 2022): 603. http://dx.doi.org/10.3390/cells11040603.

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Neurons transmit and receive information at specialized junctions called synapses. Excitatory synapses form at the junction between a presynaptic axon terminal and a postsynaptic dendritic spine. Supporting the shape and function of these junctions is a complex network of actin filaments and its regulators. Advances in microscopic techniques have enabled studies of the organization of actin at synapses and its dynamic regulation. In addition to highlighting recent advances in the field, we will provide a brief historical perspective of the understanding of synaptic actin at the synapse. We will also highlight key neuronal functions regulated by actin, including organization of proteins in the pre- and post- synaptic compartments and endocytosis of ion channels. We review the evidence that synapses contain distinct actin pools that differ in their localization and dynamic behaviors and discuss key functions for these actin pools. Finally, whole exome sequencing of humans with neurodevelopmental and psychiatric disorders has identified synaptic actin regulators as key disease risk genes. We briefly summarize how genetic variants in these genes impact neurotransmission via their impact on synaptic actin.

17

Önel, Susanne-Filiz. "Actin regulators take the reins in Drosophila myoblast fusion." Open Life Sciences 4, no. 1 (March 1, 2009): 11–18. http://dx.doi.org/10.2478/s11535-008-0059-9.

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AbstractSkeletal muscle formation, growth and repair depend on myoblast fusion events. Therefore, in-depth understanding of the underlying molecular mechanisms controlling these events that ultimately lead to skeletal muscle formation may be fundamental for developing new therapies for tissue repair. To this end, the greatest advances in furthering understanding myoblast fusion has been made in Drosophila. Recent studies have shown that transient F-actin structures, so-called actin plugs or foci, are known to form at the site of contacting myoblasts. Indeed, actin regulators of the WASP family that control the activation of the Arp2/3 complex and thereby branched F-actin formation have been demonstrated to be crucial for myoblast fusion. Myoblast-specific cell adhesion molecules seem to be involved in the recruitment of WASP family members to the site of myoblast fusion and form a Fusion-Restricted Myogenic-Adhesive Structure (FuRMAS). Currently, the exact role of the FuRMAS is not completely understood. However, recent studies indicate that WASP-dependent F-actin regulation is required for fusion pore formation as well as for the correct integration of fusing myoblasts into the growing muscle. In this review, I discuss latest cellular studies, and recent genetic and biochemical analyses on actin regulation during myoblast fusion.

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Hu, Xiaohua, and R. Dyche Mullins. "LC3 and STRAP regulate actin filament assembly by JMY during autophagosome formation." Journal of Cell Biology 218, no. 1 (November 12, 2018): 251–66. http://dx.doi.org/10.1083/jcb.201802157.

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During autophagy, actin filament networks move and remodel cellular membranes to form autophagosomes that enclose and metabolize cytoplasmic contents. Two actin regulators, WHAMM and JMY, participate in autophagosome formation, but the signals linking autophagy to actin assembly are poorly understood. We show that, in nonstarved cells, cytoplasmic JMY colocalizes with STRAP, a regulator of JMY’s nuclear functions, on nonmotile vesicles with no associated actin networks. Upon starvation, JMY shifts to motile, LC3-containing membranes that move on actin comet tails. LC3 enhances JMY’s de novo actin nucleation activity via a cryptic actin-binding sequence near JMY’s N terminus, and STRAP inhibits JMY’s ability to nucleate actin and activate the Arp2/3 complex. Cytoplasmic STRAP negatively regulates autophagy. Finally, we use purified proteins to reconstitute LC3- and JMY-dependent actin network formation on membranes and inhibition of network formation by STRAP. We conclude that LC3 and STRAP regulate JMY’s actin assembly activities in trans during autophagy.

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Shin, Myungjoo, Jolanda van Leeuwen, Charles Boone, and Anthony Bretscher. "Yeast Aim21/Tda2 both regulates free actin by reducing barbed end assembly and forms a complex with Cap1/Cap2 to balance actin assembly between patches and cables." Molecular Biology of the Cell 29, no. 8 (April 15, 2018): 923–36. http://dx.doi.org/10.1091/mbc.e17-10-0592.

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How cells balance the incorporation of actin into diverse structures is poorly understood. In budding yeast, a single actin monomer pool is used to build both actin cables involved in polarized growth and actin cortical patches involved in endocytosis. Here we report how Aim21/Tda2 is recruited to the cortical region of actin patches, where it negatively regulates actin assembly to elevate the available actin monomer pool. Aim21 has four polyproline regions and is recruited by two SH3-containing patch proteins, Bbc1 and Abp1. The C-terminal region, which is required for its function, binds Tda2. Cell biological and biochemical data reveal that Aim21/Tda2 is a negative regulator of barbed end filamentous actin (F-actin) assembly, and this activity is necessary for efficient endocytosis and plays a pivotal role in balancing the distribution of actin between cables and patches. Aim21/Tda2 also forms a complex with the F-actin barbed end capping protein Cap1/Cap2, revealing an interplay between regulators and showing the complexity of regulation of barbed end assembly.

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Vitriol, Eric A., Ariel L. Wise, Mathew E. Berginski, James R. Bamburg, and James Q. Zheng. "Instantaneous inactivation of cofilin reveals its function of F-actin disassembly in lamellipodia." Molecular Biology of the Cell 24, no. 14 (July 15, 2013): 2238–47. http://dx.doi.org/10.1091/mbc.e13-03-0156.

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Cofilin is a key regulator of the actin cytoskeleton. It can sever actin filaments, accelerate filament disassembly, act as a nucleation factor, recruit or antagonize other actin regulators, and control the pool of polymerization-competent actin monomers. In cells these actions have complex functional outputs. The timing and localization of cofilin activity are carefully regulated, and thus global, long-term perturbations may not be sufficient to probe its precise function. To better understand cofilin's spatiotemporal action in cells, we implemented chromophore-assisted laser inactivation (CALI) to instantly and specifically inactivate it. In addition to globally inhibiting actin turnover, CALI of cofilin generated several profound effects on the lamellipodia, including an increase of F-actin, a rearward expansion of the actin network, and a reduction in retrograde flow speed. These results support the hypothesis that the principal role of cofilin in lamellipodia at steady state is to break down F-actin, control filament turnover, and regulate the rate of retrograde flow.

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Grevengoed, Elizabeth E., Donald T. Fox, Julie Gates, and Mark Peifer. "Balancing different types of actin polymerization at distinct sites." Journal of Cell Biology 163, no. 6 (December 15, 2003): 1267–79. http://dx.doi.org/10.1083/jcb.200307026.

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The proto-oncogenic kinase Abelson (Abl) regulates actin in response to cell signaling. Drosophila Abl is required in the nervous system, and also in epithelial cells, where it regulates adherens junction stability and actin organization. Abl acts at least in part via the actin regulator Enabled (Ena), but the mechanism by which Abl regulates Ena is unknown. We describe a novel role for Abl in early Drosophila development, where it regulates the site and type of actin structures produced. In Abl's absence, excess actin is polymerized in apical microvilli, whereas too little actin is assembled into pseudocleavage and cellularization furrows. These effects involve Ena misregulation. In abl mutants, Ena accumulates ectopically at the apical cortex where excess actin is observed, suggesting that Abl regulates Ena's subcellular localization. We also examined other actin regulators. Loss of Abl leads to changes in the localization of the Arp2/3 complex and the formin Diaphanous, and mutations in diaphanous or capping protein β enhance abl phenotypes.

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Matsubayashi, Yutaka, Camilla Coulson-Gilmer, and Tom H. Millard. "Endocytosis-dependent coordination of multiple actin regulators is required for wound healing." Journal of Cell Biology 210, no. 3 (July 27, 2015): 419–33. http://dx.doi.org/10.1083/jcb.201411037.

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The ability to heal wounds efficiently is essential for life. After wounding of an epithelium, the cells bordering the wound form dynamic actin protrusions and/or a contractile actomyosin cable, and these actin structures drive wound closure. Despite their importance in wound healing, the molecular mechanisms that regulate the assembly of these actin structures at wound edges are not well understood. In this paper, using Drosophila melanogaster embryos, we demonstrate that Diaphanous, SCAR, and WASp play distinct but overlapping roles in regulating actin assembly during wound healing. Moreover, we show that endocytosis is essential for wound edge actin assembly and wound closure. We identify adherens junctions (AJs) as a key target of endocytosis during wound healing and propose that endocytic remodeling of AJs is required to form “signaling centers” along the wound edge that control actin assembly. We conclude that coordination of actin assembly, AJ remodeling, and membrane traffic is required for the construction of a motile leading edge during wound healing.

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Augustin, Vanessa, and Stefan Kins. "Fe65: A Scaffolding Protein of Actin Regulators." Cells 10, no. 7 (June 25, 2021): 1599. http://dx.doi.org/10.3390/cells10071599.

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The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer’s disease. All three Fe65 family members possess three highly conserved interaction domains, forming complexes with diverse binding partners that can be assigned to different cellular functions, such as transactivation of genes in the nucleus, modulation of calcium homeostasis and lipid metabolism, and regulation of the actin cytoskeleton. In this article, we rule out putative new intracellular signaling mechanisms of the APP-interacting protein Fe65 in the regulation of actin cytoskeleton dynamics in the context of various neuronal functions, such as cell migration, neurite outgrowth, and synaptic plasticity.

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Veltman, Douwe M., Jason S. King, Laura M. Machesky, and Robert H. Insall. "SCAR knockouts in Dictyostelium: WASP assumes SCAR’s position and upstream regulators in pseudopods." Journal of Cell Biology 198, no. 4 (August 13, 2012): 501–8. http://dx.doi.org/10.1083/jcb.201205058.

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Under normal conditions, the Arp2/3 complex activator SCAR/WAVE controls actin polymerization in pseudopods, whereas Wiskott–Aldrich syndrome protein (WASP) assembles actin at clathrin-coated pits. We show that, unexpectedly, Dictyostelium discoideum SCAR knockouts could still spread, migrate, and chemotax using pseudopods driven by the Arp2/3 complex. In the absence of SCAR, some WASP relocated from the coated pits to the leading edge, where it behaved with similar dynamics to normal SCAR, forming split pseudopods and traveling waves. Pseudopods colocalized with active Rac, whether driven by WASP or SCAR, though Rac was activated to a higher level in SCAR mutants. Members of the SCAR regulatory complex, in particular PIR121, were not required for WASP regulation. We thus show that WASP is able to respond to all core upstream signals and that regulators coupled through the other members of SCAR’s regulatory complex are not essential for pseudopod formation. We conclude that WASP and SCAR can regulate pseudopod actin using similar mechanisms.

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Stark, Benjamin C., M. Hunter Lanier, and John A. Cooper. "CARMIL family proteins as multidomain regulators of actin-based motility." Molecular Biology of the Cell 28, no. 13 (July 2017): 1713–23. http://dx.doi.org/10.1091/mbc.e17-01-0019.

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CARMILs are large multidomain proteins that regulate the actin-binding activity of capping protein (CP), a major capper of actin filament barbed ends in cells. CARMILs bind directly to CP and induce a conformational change that allosterically decreases but does not abolish its actin-capping activity. The CP-binding domain of CARMIL consists of the CP-interaction (CPI) and CARMIL-specific interaction (CSI) motifs, which are arranged in tandem. Many cellular functions of CARMILs require the interaction with CP; however, a more surprising result is that the cellular function of CP in cells appears to require binding to a CARMIL or another protein with a CPI motif, suggesting that CPI-motif proteins target CP and modulate its actin-capping activity. Vertebrates have three highly conserved genes and expressed isoforms of CARMIL with distinct and overlapping localizations and functions in cells. Various domains of these CARMIL isoforms interact with plasma membranes, vimentin intermediate filaments, SH3-containing class I myosins, the dual-GEF Trio, and other adaptors and signaling molecules. These biochemical properties suggest that CARMILs play a variety of membrane-associated functions related to actin assembly and signaling. CARMIL mutations and variants have been implicated in several human diseases. We focus on roles for CARMILs in signaling in addition to their function as regulators of CP and actin.

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Pimm, Morgan L., and Jessica L. Henty-Ridilla. "New twists in actin–microtubule interactions." Molecular Biology of the Cell 32, no. 3 (February 1, 2021): 211–17. http://dx.doi.org/10.1091/mbc.e19-09-0491.

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Actin filaments and microtubules are cytoskeletal polymers that participate in many vital cell functions including division, morphogenesis, phagocytosis, and motility. Despite the persistent dogma that actin filament and microtubule networks are distinct in localization, structure, and function, a growing body of evidence shows that these elements are choreographed through intricate mechanisms sensitive to either polymer. Many proteins and cellular signals that mediate actin–microtubule interactions have already been identified. However, the impact of these regulators is typically assessed with actin filament or microtubule polymers alone, independent of the other system. Further, unconventional modes and regulators coordinating actin–microtubule interactions are still being discovered. Here we examine several methods of actin–microtubule crosstalk with an emphasis on the molecular links between both polymer systems and their higher-order interactions.

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Tanna, Christine, Louisa Goss, Calvin Ludwig, and Pei-Wen Chen. "Arf•GAPs as Regulators of the Actin Cytoskeleton—An Update." International Journal of Molecular Sciences 20, no. 2 (January 21, 2019): 442. http://dx.doi.org/10.3390/ijms20020442.

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Arf•GTPase-activating proteins (Arf•GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf•GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf•GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf•GAPs. Arf•GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf•GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function.

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Hattori, Hidenori, Kulandayan K. Subramanian, and Hongbo R. Luo. "Small-Molecule Screen Identifies ROS as Key Regulators of Actin Dynamics in Neutrophils." Blood 112, no. 11 (November 16, 2008): 4641. http://dx.doi.org/10.1182/blood.v112.11.4641.4641.

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Abstract Precise spatial and temporal control of actin polymerization and depolymerization is essential for mediating various cellular processes such as migration, phagocytosis, vesicle trafficking and adhesion. In this study, we used a small-molecule functional screening approach to identify novel regulators of actin dynamics during neutrophil migration. Here we show that NADPH-oxidase dependent Reactive Oxygen Species act as negative regulators of actin polymerization. Neutrophils with pharmacologically inhibited oxidase or isolated from Chronic Granulomatous Disease (CGD) patient and mice displayed enhanced F-actin polymerization, multiple pseudopods formation and impaired chemotaxis. ROS localized to pseudopodia and inhibited actin polymerization by driving actin glutathionylation at the leading edge of migrating cells. Consistent with these in vitro results, adoptively transferred CGD murine neutrophils also showed impaired in vivo recruitment to sites of inflammation. Together, these results present a novel physiological role for ROS in regulation of action polymerization and shed new light on the pathogenesis of CGD.

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Kumpula, Esa-Pekka, and Inari Kursula. "Towards a molecular understanding of the apicomplexan actin motor: on a road to novel targets for malaria remedies?" Acta Crystallographica Section F Structural Biology Communications 71, no. 5 (April 16, 2015): 500–513. http://dx.doi.org/10.1107/s2053230x1500391x.

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Apicomplexan parasites are the causative agents of notorious human and animal diseases that give rise to considerable human suffering and economic losses worldwide. The most prominent parasites of this phylum are the malaria-causingPlasmodiumspecies, which are widespread in tropical and subtropical regions, andToxoplasma gondii, which infects one third of the world's population. These parasites share a common form of gliding motility which relies on an actin–myosin motor. The components of this motor and the actin-regulatory proteins in Apicomplexa have unique features compared with all other eukaryotes. This, together with the crucial roles of these proteins, makes them attractive targets for structure-based drug design. In recent years, several structures of glideosome components, in particular of actins and actin regulators from apicomplexan parasites, have been determined, which will hopefully soon allow the creation of a complete molecular picture of the parasite actin–myosin motor and its regulatory machinery. Here, current knowledge of the function of this motor is reviewed from a structural perspective.

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von Kalm, Laurence, and Corey Seavey. "Abstract 2461: The cell migration inhibitor dihydromotuporamine C regulates actin-myosin contractility and actin polymerization." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2461. http://dx.doi.org/10.1158/1538-7445.am2023-2461.

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Abstract The motuporamines are a promising class of anti-metastatic compounds. Dihydromotuporamine C (Motu33) has been shown to activate the small GTPase RhoA, however, little is known about subsequent downstream events leading to cell migration inhibition. In the present study, we investigated the mechanism of action of Motu33 and a synthetic derivative, Motu-(CH2)-33, in Drosophila by manipulating the gene dose of positive and negative regulators of actin dynamics. Consistent with previous findings, reduced gene dose of Rho1 (the Drosophila RhoA ortholog) attenuates motuporamine activity, confirming that RhoA/Rho1 is targeted by these compounds. Actin-myosin contraction is controlled by the RhoA-ROCK-myosin regulatory light chain (MRLC) pathway. Reduced gene dose of the myosin binding subunit of myosin phosphatase, a negative regulator of the RhoA-ROCK-MRLC pathway, enhances motuporamine activity indicating that the motuporamines stimulate actin-myosin contraction through activation of the myosin regulatory light chain. RhoA also activates diaphanous (dia) to control actin polymerization. Surprisingly, reduced gene dose of dia enhances motuporamine activity, suggesting that the motuporamines act on dia in a RhoA-independent manner. Reduction in gene dose of the Drosophila Rac orthologs also enhances motuporamine activity. In contrast, motuporamine activity is unaltered by reduced gene dose of slingshot (ssh) which acts to trigger actin severing and depolymerization. Since ssh is directly regulated by Rac, the enhanced activity of motuporamines observed when Rac gene dose is reduced may reflect an indirect mode of action on the Rac GTPases leading to increased RhoA activity. In summary, these findings demonstrate that motuporamines act through RhoA and diaphanous to regulate actin-myosin contractility and actin polymerization. Citation Format: Laurence von Kalm, Corey Seavey. The cell migration inhibitor dihydromotuporamine C regulates actin-myosin contractility and actin polymerization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2461.

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Banerjee, Jayashree, and Philip B. Wedegaertner. "Identification of a Novel Sequence in PDZ-RhoGEF That Mediates Interaction with the Actin Cytoskeleton." Molecular Biology of the Cell 15, no. 4 (April 2004): 1760–75. http://dx.doi.org/10.1091/mbc.e03-07-0527.

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Small GTPases of the Rho family are crucial regulators of actin cytoskeleton rearrangements. Rho is activated by members of the Rho guanine-nucleotide exchange factor (GEF) family; however, mechanisms that regulate RhoGEFs are not well understood. This report demonstrates that PDZ-RhoGEF, a member of a subfamily of RhoGEFs that contain regulator of G protein signaling domains, is partially localized at or near the plasma membranes in 293T, COS-7, and Neuro2a cells, and this localization is coincident with cortical actin. Disruption of the cortical actin cytoskeleton in cells by using latrunculin B prevents the peri-plasma membrane localization of PDZ-RhoGEF. Coimmunoprecipitation and F-actin cosedimentation assays demonstrate that PDZ-RhoGEF binds to actin. Extensive deletion mutagenesis revealed the presence of a novel 25-amino acid sequence in PDZ-RhoGEF, located at amino acids 561–585, that is necessary and sufficient for localization to the actin cytoskeleton and interaction with actin. Last, PDZ-RhoGEF mutants that fail to interact with the actin cytoskeleton display enhanced Rho-dependent signaling compared with wild-type PDZ-RhoGEF. These results identify interaction with the actin cytoskeleton as a novel function for PDZ-RhoGEF, thus implicating actin interaction in organizing PDZ-RhoGEF signaling.

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Niles, Brad J., and Ted Powers. "TOR complex 2–Ypk1 signaling regulates actin polarization via reactive oxygen species." Molecular Biology of the Cell 25, no. 24 (December 2014): 3962–72. http://dx.doi.org/10.1091/mbc.e14-06-1122.

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The evolutionarily conserved mTOR complex 2 (mTORC2) signaling pathway is an important regulator of actin cytoskeletal architecture and, as such, is a candidate target for preventing cancer cell motility and invasion. Remarkably, the precise mechanism(s) by which mTORC2 regulates the actin cytoskeleton have remained elusive. Here we show that in budding yeast, TORC2 and its downstream kinase Ypk1 regulate actin polarization by controlling reactive oxygen species (ROS) accumulation. Specifically, we find that TORC2-Ypk1 regulates actin polarization both by vacuole-related ROS, controlled by the phospholipid flippase kinase Fpk1 and sphingolipids, and by mitochondria-mediated ROS, controlled by the PKA subunit Tpk3. In addition, we find that the protein kinase C (Pkc1)/MAPK cascade, a well-established regulator of actin, acts downstream of Ypk1 to regulate ROS, in part by promoting degradation of the oxidative stress responsive repressor, cyclin C. Furthermore, we show that Ypk1 regulates Pkc1 activity through proper localization of Rom2 at the plasma membrane, which is also dependent on Fpk1 and sphingolipids. Together these findings demonstrate important links between TORC2/Ypk1 signaling, Fpk1, sphingolipids, Pkc1, and ROS as regulators of actin and suggest that ROS may play an important role in mTORC2-dependent dysregulation of the actin cytoskeleton in cancer cells.

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Grintsevich, Elena E. "Effects of neuronal drebrin on actin dynamics." Biochemical Society Transactions 49, no. 2 (March 19, 2021): 685–92. http://dx.doi.org/10.1042/bst20200577.

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Drebrin is a key regulator of actin cytoskeleton in neuronal cells which is critical for synaptic plasticity, neuritogenesis, and neuronal migration. It is also known to orchestrate a cross-talk between actin and microtubules. Decreased level of drebrin is a hallmark of multiple neurodegenerative disorders such as Alzheimer's disease. Despite its established importance in health and disease, we still have a lot to learn about drebrin's interactome and its effects on cytoskeletal dynamics. This review aims to summarize the recently reported novel effects of drebrin on actin and its regulators. Here I will also reflect on the most recent progress made in understanding of the role of drebrin isoforms and posttranslational modifications on its functionality.

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Holliday, L. Shannon, Lorraine Perciliano de Faria, and Wellington J. Rody. "Actin and Actin-Associated Proteins in Extracellular Vesicles Shed by Osteoclasts." International Journal of Molecular Sciences 21, no. 1 (December 25, 2019): 158. http://dx.doi.org/10.3390/ijms21010158.

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Extracellular vesicles (EVs) are shed by all eukaryotic cells and have emerged as important intercellular regulators. EVs released by osteoclasts were recently identified as important coupling factors in bone remodeling. They are shed as osteoclasts resorb bone and stimulate osteoblasts to form bone to replace the bone resorbed. We reported the proteomic content of osteoclast EVs with data from two-dimensional, high resolution liquid chromatography/mass spectrometry. In this article, we examine in detail the actin and actin-associated proteins found in osteoclast EVs. Like EVs from other cell types, actin and various actin-associated proteins were abundant. These include components of the polymerization machinery, myosin mechanoenzymes, proteins that stabilize or depolymerize microfilaments, and actin-associated proteins that are involved in regulating integrins. The selective incorporation of actin-associated proteins into osteoclast EVs suggests that they have roles in the formation of EVs and/or the regulatory signaling functions of the EVs. Regulating integrins so that they bind extracellular matrix tightly, in order to attach EVs to the extracellular matrix at specific locations in organs and tissues, is one potential active role for actin-associated proteins in EVs.

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Yamamoto, Takaharu, Junko Mochida, Jun Kadota, Miyoko Takeda, Erfei Bi, and Kazuma Tanaka. "Initial Polarized Bud Growth by Endocytic Recycling in the Absence of Actin Cable–dependent Vesicle Transport in Yeast." Molecular Biology of the Cell 21, no. 7 (April 2010): 1237–52. http://dx.doi.org/10.1091/mbc.e09-05-0412.

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The assembly of filamentous actin is essential for polarized bud growth in budding yeast. Actin cables, which are assembled by the formins Bni1p and Bnr1p, are thought to be the only actin structures that are essential for budding. However, we found that formin or tropomyosin mutants, which lack actin cables, are still able to form a small bud. Additional mutations in components for cortical actin patches, which are assembled by the Arp2/3 complex to play a pivotal role in endocytic vesicle formation, inhibited this budding. Genes involved in endocytic recycling were also required for small-bud formation in actin cable-less mutants. These results suggest that budding yeast possesses a mechanism that promotes polarized growth by local recycling of endocytic vesicles. Interestingly, the type V myosin Myo2p, which was thought to use only actin cables to track, also contributed to budding in the absence of actin cables. These results suggest that some actin network may serve as the track for Myo2p-driven vesicle transport in the absence of actin cables or that Myo2p can function independent of actin filaments. Our results also show that polarity regulators including Cdc42p were still polarized in mutants defective in both actin cables and cortical actin patches, suggesting that the actin cytoskeleton does not play a major role in cortical assembly of polarity regulators in budding yeast.

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Tian, Yufeng, Xinyong Tian, Grzegorz Gawlak, Nicolene Sarich, David B. Sacks, Anna A. Birukova, and Konstantin G. Birukov. "Role of IQGAP1 in endothelial barrier enhancement caused by OxPAPC." American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no. 4 (October 1, 2016): L800—L809. http://dx.doi.org/10.1152/ajplung.00095.2016.

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Oxidized 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphatidylcholine (OxPAPC) attenuates agonist-induced endothelial cell (EC) permeability and increases pulmonary endothelial barrier function via enhancement of both the peripheral actin cytoskeleton and cell junctions mediated by Rac1 and Cdc42 GTPases. This study evaluated the role for the multifunctional Rac1/Cdc42 effector and regulator, IQ domain containing GTPase-activating protein (IQGAP1), as a molecular transducer of the OxPAPC-mediated EC barrier-enhancing signal. IQGAP1 knockdown in endothelial cells by gene-specific small-interfering RNA abolished OxPAPC-induced enlargement of VE-cadherin-positive adherens junctions, suppressed peripheral accumulation of actin polymerization regulators, namely cortactin, neural Wiskott-Aldrich syndrome protein (N-WASP), and actin-related protein 3, and attenuated remodeling of the peripheral actin cytoskeleton. Inhibition of OxPAPC-induced barrier enhancement by IQGAP1 knockdown was due to suppressed Rac1 and Cdc42 activation. Expression of an IQGAP1 truncated mutant showed that the GTPase regulatory domain of IQGAP1 was essential for the OxPAPC-induced membrane localization of cortactin, adherens junction proteins VE-cadherin and p120-catenin, as well as for EC permeability response. IQGAP1 knockdown attenuated the protective effect of OxPAPC against thrombin-induced cell contraction, cell junction disruption, and EC permeability. These results demonstrate for the first time the role of IQGAP1 as a critical transducer of OxPAPC-induced Rac1/Cdc42 signaling to the actin cytoskeleton and adherens junctions, which promotes cortical cytoskeletal remodeling and EC barrier-protective effects of oxidized phospholipids.

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Naj, Xenia, Ann-Kathrin Hoffmann, Mirko Himmel, and Stefan Linder. "The Formins FMNL1 and mDia1 Regulate Coiling Phagocytosis of Borrelia burgdorferi by Primary Human Macrophages." Infection and Immunity 81, no. 5 (March 4, 2013): 1683–95. http://dx.doi.org/10.1128/iai.01411-12.

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ABSTRACTSpirochetes of theBorrelia burgdorferisensu latocomplex are the causative agent of Lyme borreliosis, a tick-borne infectious disease primarily affecting the skin, nervous system, and joints. During infection, macrophages and dendritic cells are the first immune cells to encounter invading borreliae. Phagocytosis and intracellular processing ofBorreliaby these cells is thus decisive for the eventual outcome of infection. Phagocytic uptake ofBorreliaby macrophages proceeds preferentially through coiling phagocytosis, which is characterized by actin-rich unilateral pseudopods that capture and enwrap spirochetes. Actin-dependent growth of these pseudopods necessitatesde novonucleation of actin filaments, which is regulated by actin-nucleating factors such as Arp2/3 complex. Here, we demonstrate that, in addition, also actin-regulatory proteins of the formin family are important for uptake of borreliae by primary human macrophages. Using immunofluorescence, live-cell imaging, and ratiometric analysis, we find specific enrichment of the formins FMNL1 and mDia1 at macrophage pseudopods that are in contact with borreliae. Consistently, small interfering RNA (siRNA)-mediated knockdown of FMNL1 or mDia1 leads to decreased formation ofBorrelia-induced pseudopods and to decreased internalization of borreliae by macrophages. Our results suggest that macrophage coiling phagocytosis is a complex process involving several actin nucleation/regulatory factors. They also point specifically to the formins mDia1 and FMNL1 as novel regulators of spirochete uptake by human immune cells.

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Föger, Niko, André Jenckel, Zane Orinska, Kyeong-Hee Lee, Andrew C. Chan, and Silvia Bulfone-Paus. "Differential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b." Journal of Experimental Medicine 208, no. 9 (August 15, 2011): 1777–87. http://dx.doi.org/10.1084/jem.20101757.

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Mast cell (MC) activation via aggregation of the high affinity IgE receptor (FcεRI) causes degranulation and release of proinflammatory mediators in a process that involves the reorganization of the actin cytoskeleton. However, the regulatory pathways and the molecular links between cytoskeletal changes and MC function are incompletely understood. In this study, we provide genetic evidence for a critical role of the actin-regulatory proteins Coronin1a (Coro1a) and Coro1b on exocytic pathways in MCs: Coro1a−/− bone marrow–derived MCs exhibit increased FcεRI-mediated degranulation of secretory lysosomes but significantly reduced secretion of cytokines. Hyperdegranulation of Coro1a−/− MCs is further augmented by the additional loss of Coro1b. In vivo, Coro1a−/−Coro1b−/− mice displayed enhanced passive cutaneous anaphylaxis. Functional reconstitution assays revealed that the inhibitory effect of Coro1a on MC degranulation strictly correlates with cortical localization of Coro1a, requires its filamentous actin–binding activity, and is regulated by phosphorylation of Ser2 of Coro1a. Thus, coronin proteins, and in turn the actin cytoskeleton, exhibit a functional dichotomy as differential regulators of degranulation versus cytokine secretion in MC biology.

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Kepser, Lara-Jane, Fidan Damar, Teresa De Cicco, Christine Chaponnier, Tomasz J. Prószyński, Axel Pagenstecher, and Marco B. Rust. "CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function." Proceedings of the National Academy of Sciences 116, no. 17 (April 8, 2019): 8397–402. http://dx.doi.org/10.1073/pnas.1813351116.

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Actin filaments (F-actin) are key components of sarcomeres, the basic contractile units of skeletal muscle myofibrils. A crucial step during myofibril differentiation is the sequential exchange of α-actin isoforms from smooth muscle (α-SMA) and cardiac (α-CAA) to skeletal muscle α-actin (α-SKA) that, in mice, occurs during early postnatal life. This “α-actin switch” requires the coordinated activity of actin regulators because it is vital that sarcomere structure and function are maintained during differentiation. The molecular machinery that controls the α-actin switch, however, remains enigmatic. Cyclase-associated proteins (CAP) are a family of actin regulators with largely unknown physiological functions. We here report a function for CAP2 in regulating the α-actin exchange during myofibril differentiation. This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice. The delay in the α-actin switch coincided with the onset of motor function deficits and histopathological changes including a high frequency of type IIB ring fibers. Our data suggest that subtle disturbances of postnatal F-actin remodeling are sufficient for predisposing muscle fibers to form ring fibers. Cofilin2, a putative CAP2 interaction partner, has been recently implicated in myofibril actin cytoskeleton differentiation, and the myopathies in cofilin2 and CAP2 mutant mice showed striking similarities. We therefore propose a model in which CAP2 and cofilin2 cooperate in actin regulation during myofibril differentiation.

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Wilton, Katelynn Marie, and Daniel D. Billadeau. "Vasodilator Stimulated Phosphoprotein (VASP)-Mediated Actin Polymerization Drives Natural Killer Cell Granule Convergence." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 170.7. http://dx.doi.org/10.4049/jimmunol.200.supp.170.7.

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Abstract Natural killer (NK) cells eliminate transformed and malignant cells through a highly orchestrated series of actin and microtubule cytoskeletal rearrangements, culminating in the secretion of preformed lytic granules. Despite the importance of actin and microtubules, the roles of many molecular cytoskeletal regulators in this process have not yet been ascertained. In this study, we investigated the role of Vasodilator Stimulated Phosphoprotein (VASP), an actin regulatory protein, in NK cell-mediated cytotoxicity. Interestingly, we found that depletion of VASP inhibits NK cell cytotoxicity and that VASP co-localizes with F-actin at the NK cell – target cell cytotoxic synapse. Surprisingly, despite their co-localization, VASP depletion did not affect either F-actin accumulation at the cytotoxic synapse or conjugate formation. Instead, we found that a minority of VASP localized and biochemically co-purified with cytolytic granules. Although VASP knockdown did not affect microtubule organizing center (MTOC) polarization, it did dramatically impact lytic granule convergence to the MTOC. Significantly, VASP depletion decreased F-actin accumulation on cytolytic granules and depolymerization of F-actin with Latrunculin A impaired lytic granule convergence. Taken together, these results demonstrate a novel requirement for VASP-mediated actin polymerization in NK cell granule convergence and cytotoxicity and highlight a role for F-actin in lytic granule convergence.

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Bartolini, Francesca, Nagendran Ramalingam, and Gregg G. Gundersen. "Actin-capping protein promotes microtubule stability by antagonizing the actin activity of mDia1." Molecular Biology of the Cell 23, no. 20 (October 15, 2012): 4032–40. http://dx.doi.org/10.1091/mbc.e12-05-0338.

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In migrating fibroblasts, RhoA and its effector mDia1 regulate the selective stabilization of microtubules (MTs) polarized in the direction of migration. The conserved formin homology 2 domain of mDia1 is involved both in actin polymerization and MT stabilization, and the relationship between these two activities is unknown. We found that latrunculin A (LatA) and jasplakinolide, actin drugs that release mDia1 from actin filament barbed ends, stimulated stable MT formation in serum-starved fibroblasts and caused a redistribution of mDia1 onto MTs. Knockdown of mDia1 by small interfering RNA (siRNA) prevented stable MT induction by LatA, whereas blocking upstream Rho or integrin signaling had no effect. In search of physiological regulators of mDia1, we found that actin-capping protein induced stable MTs in an mDia1-dependent manner and inhibited the translocation of mDia on the ends of growing actin filaments. Knockdown of capping protein by siRNA reduced stable MT levels in proliferating cells and in starved cells stimulated with lysophosphatidic acid. These results show that actin-capping protein is a novel regulator of MT stability that functions by antagonizing mDia1 activity toward actin filaments and suggest a novel form of actin–MT cross-talk in which a single factor acts sequentially on actin and MTs.

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Seth, Abhinav, Chinatsu Otomo, and Michael K. Rosen. "Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLα and mDia1." Journal of Cell Biology 174, no. 5 (August 28, 2006): 701–13. http://dx.doi.org/10.1083/jcb.200605006.

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Diaphanous-related formins (DRFs) are key regulators of actin cytoskeletal dynamics whose in vitro actin assembly activities are thought to be regulated by autoinhibition. However, the in vivo consequences of autoinhibition and the involvement of DRFs in specific biological processes are not well understood. In this study, we show that in the DRFs FRLα (formin-related gene in leukocytes α) and mouse diaphanous 1, autoinhibition regulates a novel membrane localization activity in vivo as well as actin assembly activity in vitro. In FRLα, the Rho family guanosine triphosphatase Cdc42 relieves the autoinhibition of both membrane localization and biochemical actin assembly activities. FRLα is required for efficient Fc-γ receptor–mediated phagocytosis and is recruited to the phagocytic cup by Cdc42. These results suggest that mutual autoinhibition of biochemical activity and cellular localization may be a general regulatory principle for DRFs and demonstrate a novel role for formins in immune function.

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Mostowy, Serge, and Pascale Cossart. "Septins as key regulators of actin based processes in bacterial infection." Biological Chemistry 392, no. 8-9 (August 1, 2011): 831–35. http://dx.doi.org/10.1515/bc.2011.078.

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Abstract Many pathogens have evolved a variety of mechanisms to exploit the host-cell actin cytoskeleton during infection, either to enter into cells or to move within cells. These events have been investigated and documented in detail. Yet, a complete picture of the molecules and mechanisms regulating entry and intracellular movement remains to be established. Here we present a series of studies revealing that in addition to actin rearrangements the host cell also employs septins, a relatively newly characterized component of the cell cyto-skeleton, to regulate bacterial entry and restrict the dissemination of cytosolic bacteria. The challenge now is to decipher the precise role of septins during actin rearrangements and how these different cytoskeleton components orchestrate infection processes.

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Molinie, Nicolas, and Alexis Gautreau. "The Arp2/3 Regulatory System and Its Deregulation in Cancer." Physiological Reviews 98, no. 1 (January 1, 2018): 215–38. http://dx.doi.org/10.1152/physrev.00006.2017.

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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.

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Randazzo, Paul A., Hiroki Inoue, and Sanita Bharti. "Arf GAPs as regulators of the actin cytoskeleton." Biology of the Cell 99, no. 10 (October 2007): 583–600. http://dx.doi.org/10.1042/bc20070034.

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Edwards, Marc, Adam Zwolak, Dorothy A. Schafer, David Sept, Roberto Dominguez, and John A. Cooper. "Capping protein regulators fine-tune actin assembly dynamics." Nature Reviews Molecular Cell Biology 15, no. 10 (September 10, 2014): 677–89. http://dx.doi.org/10.1038/nrm3869.

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Watanabe, Takashi, Shujie Wang, and Kozo Kaibuchi. "IQGAPs as Key Regulators of Actin-cytoskeleton Dynamics." Cell Structure and Function 40, no. 2 (2015): 69–77. http://dx.doi.org/10.1247/csf.15003.

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Rozenblum, Guido T., and Mario Gimona. "Calponins: Adaptable modular regulators of the actin cytoskeleton." International Journal of Biochemistry & Cell Biology 40, no. 10 (January 2008): 1990–95. http://dx.doi.org/10.1016/j.biocel.2007.07.010.

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Nowotarski, Stephanie H., Natalie McKeon, Rachel J. Moser, and Mark Peifer. "The actin regulators Enabled and Diaphanous direct distinct protrusive behaviors in different tissues during Drosophila development." Molecular Biology of the Cell 25, no. 20 (October 15, 2014): 3147–65. http://dx.doi.org/10.1091/mbc.e14-05-0951.

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Actin-based protrusions are important for signaling and migration during development and homeostasis. Defining how different tissues in vivo craft diverse protrusive behaviors using the same genomic toolkit of actin regulators is a current challenge. The actin elongation factors Diaphanous and Enabled both promote barbed-end actin polymerization and can stimulate filopodia in cultured cells. However, redundancy in mammals and Diaphanous’ role in cytokinesis limited analysis of whether and how they regulate protrusions during development. We used two tissues driving Drosophila dorsal closure—migratory leading-edge (LE) and nonmigratory amnioserosal (AS) cells—as models to define how cells shape distinct protrusions during morphogenesis. We found that nonmigratory AS cells produce filopodia that are morphologically and dynamically distinct from those of LE cells. We hypothesized that differing Enabled and/or Diaphanous activity drives these differences. Combining gain- and loss-of-function with quantitative approaches revealed that Diaphanous and Enabled each regulate filopodial behavior in vivo and defined a quantitative “fingerprint”—the protrusive profile—which our data suggest is characteristic of each actin regulator. Our data suggest that LE protrusiveness is primarily Enabled driven, whereas Diaphanous plays the primary role in the AS, and reveal each has roles in dorsal closure, but its robustness ensures timely completion in their absence.

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Hsiao, Bo-Yuan, Chia-Hsin Chen, Ho-Yi Chi, Pei-Ru Yen, Ying-Zhen Yu, Chia-Hsin Lin, Te-Ling Pang, et al. "Human Costars Family Protein ABRACL Modulates Actin Dynamics and Cell Migration and Associates with Tumorigenic Growth." International Journal of Molecular Sciences 22, no. 4 (February 18, 2021): 2037. http://dx.doi.org/10.3390/ijms22042037.

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Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.

Journal articles on the topic 'Actin regulators'

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