Journal articles on the topic 'Actin cytoskeleton modulation'
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1
Uray, Karen, Evelin Major, and Beata Lontay. "MicroRNA Regulatory Pathways in the Control of the Actin–Myosin Cytoskeleton." Cells 9, no. 7 (July 9, 2020): 1649. http://dx.doi.org/10.3390/cells9071649.
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MicroRNAs (miRNAs) are key modulators of post-transcriptional gene regulation in a plethora of processes, including actin–myosin cytoskeleton dynamics. Recent evidence points to the widespread effects of miRNAs on actin–myosin cytoskeleton dynamics, either directly on the expression of actin and myosin genes or indirectly on the diverse signaling cascades modulating cytoskeletal arrangement. Furthermore, studies from various human models indicate that miRNAs contribute to the development of various human disorders. The potentially huge impact of miRNA-based mechanisms on cytoskeletal elements is just starting to be recognized. In this review, we summarize recent knowledge about the importance of microRNA modulation of the actin–myosin cytoskeleton affecting physiological processes, including cardiovascular function, hematopoiesis, podocyte physiology, and osteogenesis.
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Ganusova, Elena E., Laura N. Ozolins, Srishti Bhagat, Gary P. Newnam, Renee D. Wegrzyn, Michael Y. Sherman, and Yury O. Chernoff. "Modulation of Prion Formation, Aggregation, and Toxicity by the Actin Cytoskeleton in Yeast." Molecular and Cellular Biology 26, no. 2 (January 15, 2006): 617–29. http://dx.doi.org/10.1128/mcb.26.2.617-629.2006.
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ABSTRACT Self-perpetuating protein aggregates transmit prion diseases in mammals and heritable traits in yeast. De novo prion formation can be induced by transient overproduction of the corresponding prion-forming protein or its prion domain. Here, we demonstrate that the yeast prion protein Sup35 interacts with various proteins of the actin cortical cytoskeleton that are involved in endocytosis. Sup35-derived aggregates, generated in the process of prion induction, are associated with the components of the endocytic/vacuolar pathway. Mutational alterations of the cortical actin cytoskeleton decrease aggregation of overproduced Sup35 and de novo prion induction and increase prion-related toxicity in yeast. Deletion of the gene coding for the actin assembly protein Sla2 is lethal in cells containing the prion isoforms of both Sup35 and Rnq1 proteins simultaneously. Our data are consistent with a model in which cytoskeletal structures provide a scaffold for generation of large aggregates, resembling mammalian aggresomes. These aggregates promote prion formation. Moreover, it appears that the actin cytoskeleton also plays a certain role in counteracting the toxicity of the overproduced potentially aggregating proteins.
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Morachevskaya, Elena A., and Anastasia V. Sudarikova. "Actin dynamics as critical ion channel regulator: ENaC and Piezo in focus." American Journal of Physiology-Cell Physiology 320, no. 5 (May 1, 2021): C696—C702. http://dx.doi.org/10.1152/ajpcell.00368.2020.
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Ion channels in plasma membrane play a principal role in different physiological processes, including cell volume regulation, signal transduction, and modulation of membrane potential in living cells. Actin-based cytoskeleton, which exists in a dynamic balance between monomeric and polymeric forms (globular and fibrillar actin), can be directly or indirectly involved in various cellular responses including modulation of ion channel activity. In this mini-review, we present an overview of the role of submembranous actin dynamics in the regulation of ion channels in excitable and nonexcitable cells. Special attention is focused on the important data about the involvement of actin assembly/disassembly and some actin-binding proteins in the control of the epithelial Na+ channel (ENaC) and mechanosensitive Piezo channels whose integral activity has a potential impact on membrane transport and multiple coupled cellular reactions. Growing evidence suggests that actin elements of the cytoskeleton can represent a “converging point” of various signaling pathways modulating the activity of ion transport proteins in cell membranes.
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Gokina, Natalia I., and George Osol. "Actin cytoskeletal modulation of pressure-induced depolarization and Ca2+ influx in cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 4 (April 1, 2002): H1410—H1420. http://dx.doi.org/10.1152/ajpheart.00441.2001.
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The objective of this study was to examine the role of the actin cytoskeleton in the development of pressure-induced membrane depolarization and Ca2+ influx underlying myogenic constriction in cerebral arteries. Elevating intraluminal pressure from 10 to 60 mmHg induced membrane depolarization, increased intracellular cytosolic Ca2+ concentration ([Ca2+]i) and elicited myogenic constriction in both intact and denuded rat posterior cerebral arteries. Pretreatment with cytochalasin D (5 μM) or latrunculin A (3 μM) abolished constriction but enhanced the [Ca2+]i response; similarly, acute application of cytochalasin D to vessels with tone, or in the presence of 60 mM K+, elicited relaxation accompanied by an increase in [Ca2+]i. The effects of cytochalasin D were inhibited by nifedipine (3 μM), demonstrating that actin cytoskeletal disruption augments Ca2+ influx through voltage-sensitive L-type Ca2+ channels. Finally, pressure-induced depolarization was enhanced in the presence of cytochalasin D, further substantiating a role for the actin cytoskeleton in the modulation of ion channel function. Together, these results implicate vascular smooth muscle actin cytoskeletal dynamics in the control of cerebral artery diameter through their influence on membrane potential as well as via a direct effect on L-type Ca2+ channels.
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Ebstrup, Malene Laage, Catarina Dias, Anne Sofie Busk Heitmann, Stine Lauritzen Sønder, and Jesper Nylandsted. "Actin Cytoskeletal Dynamics in Single-Cell Wound Repair." International Journal of Molecular Sciences 22, no. 19 (October 8, 2021): 10886. http://dx.doi.org/10.3390/ijms221910886.
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The plasma membrane protects the eukaryotic cell from its surroundings and is essential for cell viability; thus, it is crucial that membrane disruptions are repaired quickly to prevent immediate dyshomeostasis and cell death. Accordingly, cells have developed efficient repair mechanisms to rapidly reseal ruptures and reestablish membrane integrity. The cortical actin cytoskeleton plays an instrumental role in both plasma membrane resealing and restructuring in response to damage. Actin directly aids membrane repair or indirectly assists auxiliary repair mechanisms. Studies investigating single-cell wound repair have often focused on the recruitment and activation of specialized repair machinery, despite the undeniable need for rapid and dynamic cortical actin modulation; thus, the role of the cortical actin cytoskeleton during wound repair has received limited attention. This review aims to provide a comprehensive overview of membrane repair mechanisms directly or indirectly involving cortical actin cytoskeletal remodeling.
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Radhakrishnan, Girish K., and Gary A. Splitter. "Modulation of host microtubule dynamics by pathogenic bacteria." BioMolecular Concepts 3, no. 6 (December 1, 2012): 571–80. http://dx.doi.org/10.1515/bmc-2012-0030.
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AbstractThe eukaryotic cytoskeleton is a vulnerable target of many microbial pathogens during the course of infection. Rearrangements of host cytoskeleton benefit microbes in various stages of their infection cycle such as invasion, motility, and persistence. Bacterial pathogens deliver a number of effector proteins into host cells for modulating the dynamics of actin and microtubule cytoskeleton. Alteration of the actin cytoskeleton is generally achieved by bacterial effectors that target the small GTPases of the host. Modulation of microtubule dynamics involves direct interaction of effector proteins with the subunits of microtubules or recruiting cellular proteins that affect microtubule dynamics. This review will discuss effector proteins from animal and human bacterial pathogens that either destabilize or stabilize host microtubules to advance the infectious process. A compilation of these research findings will provide an overview of known and unknown strategies used by various bacterial effectors to modulate the host microtubule dynamics. The present review will undoubtedly help direct future research to determine the mechanisms of action of many bacterial effector proteins and contribute to understanding the survival strategies of diverse adherent and invasive bacterial pathogens.
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Danninger, C., and M. Gimona. "Live dynamics of GFP-calponin: isoform-specific modulation of the actin cytoskeleton and autoregulation by C-terminal sequences." Journal of Cell Science 113, no. 21 (November 1, 2000): 3725–36. http://dx.doi.org/10.1242/jcs.113.21.3725.
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The calponin family of F-actin-, tropomyosin- and calmodulin-binding proteins currently comprises three genetic variants. Their functional roles implicated from in vitro studies include the regulation of actomyosin interactions in smooth muscle cells (h1 calponin), cytoskeletal organisation in non-muscle cells (h2 calponin) and the control of neurite outgrowth (acidic calponin). We have now investigated the effects of calponin (CaP) isoforms and their C-terminal deletion mutants on the actin cytoskeleton by time lapse video microscopy of GFP fusion proteins in living smooth muscle cells and fibroblasts. It is shown that h1 CaP associates with the actin stress fibers in the more central part of the cell, whereas h2 CaP localizes to the ends of stress fibres and in the motile lamellipodial protrusions of spreading cells. Cells expressing h2 CaP spread more efficiently than those expressing h1 CaP and expression of GFP h1 CaP resulted in reduced cell motility in wound healing experiments. Notably, expression of GFP h1 CaP, but not GFP h2 CaP, conferred increased resistance of the actin cytoskeleton to the actin polymerization antagonists cytochalasin B and latrunculin B, as well as to the protein kinase inhibitors H7-dihydrochloride and rho-kinase inhibitor Y-27632. These data point towards a dual role of CaP in the stabilization and regulation of the actin cytoskeleton in vivo. Deletion studies further identify an autoregulatory role for the unique C-terminal tail sequences in the respective CaP isoforms.
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Chifflet, Silvia, and Julio A. Hernández. "The Plasma Membrane Potential and the Organization of the Actin Cytoskeleton of Epithelial Cells." International Journal of Cell Biology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/121424.
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The establishment and maintenance of the polarized epithelial phenotype require a characteristic organization of the cytoskeletal components. There are many cellular effectors involved in the regulation of the cytoskeleton of epithelial cells. Recently, modifications in the plasma membrane potential (PMP) have been suggested to participate in the modulation of the cytoskeletal organization of epithelia. Here, we review evidence showing that changes in the PMP of diverse epithelial cells promote characteristic modifications in the cytoskeletal organization, with a focus on the actin cytoskeleton. The molecular paths mediating these effects may include voltage-sensitive integral membrane proteins and/or peripheral proteins sensitive to surface potentials. The voltage dependence of the cytoskeletal organization seems to have implications in several physiological processes, including epithelial wound healing and apoptosis.
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Müller, Thorsten, Caoimhin G. Concannon, Manus W. Ward, Ciara M. Walsh, Anca L. Tirniceriu, Florian Tribl, Donat Kögel, Jochen H. M. Prehn, and Rupert Egensperger. "Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)." Molecular Biology of the Cell 18, no. 1 (January 2007): 201–10. http://dx.doi.org/10.1091/mbc.e06-04-0283.
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Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of β-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD). Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including α2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system.
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Pagliaro, L., and D. L. Taylor. "2-Deoxyglucose and cytochalasin D modulate aldolase mobility in living 3T3 cells." Journal of Cell Biology 118, no. 4 (August 15, 1992): 859–63. http://dx.doi.org/10.1083/jcb.118.4.859.
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Approximately 23% of the glycolytic enzyme aldolase in the perinuclear region of Swiss 3T3 cells is immobile as measured by FRAP. Previous studies suggest that the immobile fraction may be associated with the actin cytoskeleton (Pagliaro, L. and D. L. Taylor. 1988. J. Cell Biol. 107:981-991), and it has been proposed that the association of some glycolytic enzymes with the cytoskeleton could have functional significance, perhaps involving a fundamental relationship between glycolysis, cytoplasmic organization, and cell motility. We have tested the effect of a key glycolytic inhibitor and an actin cytoskeletal modulator on the mobility of aldolase in living cells directly, using fluorescent analog cytochemistry and FRAP. We report here that the competitive hexokinase inhibitor 2-deoxyglucose releases the bound fraction of aldolase in 3T3 cells within 10 min, and that this process is reversible upon washout of the inhibitor. A similar result is produced with the actin-binding agent, cytochalasin D. These results are consistent with models in which glycolytic enzymes are not exclusively diffusion-limited, soluble proteins, but may exist partially in the solid phase of cytoplasm. Such organization has significant implications for both the modulation of cytoplasmic structure and for cellular metabolism.
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Hordijk, P. L., E. Anthony, F. P. Mul, R. Rientsma, L. C. Oomen, and D. Roos. "Vascular-endothelial-cadherin modulates endothelial monolayer permeability." Journal of Cell Science 112, no. 12 (June 15, 1999): 1915–23. http://dx.doi.org/10.1242/jcs.112.12.1915.
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Vascular endothelial (VE)-cadherin is the endothelium-specific member of the cadherin family of homotypic cell adhesion molecules. VE-cadherin, but not the cell adhesion molecule platelet/endothelial cell adhesion molecule (PECAM-1), markedly colocalizes with actin stress fibers at cell-cell junctions between human umbilical vein endothelial cells. Inhibition of VE-cadherin-mediated, but not PECAM-1-mediated, adhesion induced reorganization of the actin cytoskeleton, loss of junctional VE-cadherin staining and loss of cell-cell adhesion. In functional assays, inhibition of VE-cadherin caused increased monolayer permeability and enhanced neutrophil transendothelial migration. In a complementary set of experiments, modulation of the actin cytoskeleton was found to strongly affect VE-cadherin distribution. Brief stimulation of the beta2-adrenergic receptor with isoproterenol induced a loss of actin stress fibers resulting in a linear, rather than ‘jagged’, VE-cadherin distribution. The concomitant, isoproterenol-induced, reduction in monolayer permeability was alleviated by a VE-cadherin-blocking antibody. Finally, cytoskeletal reorganization resulting from the inactivation of p21Rho caused a diffuse localization of VE-cadherin, which was accompanied by reduced cell-cell adhesion. Together, these data show that monolayer permeability and neutrophil transendothelial migration are modulated by VE-cadherin-mediated cell-cell adhesion, which is in turn controlled by the dynamics of the actin cytoskeleton.
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Mattila, Pieta K., Facundo D. Batista, and Bebhinn Treanor. "Dynamics of the actin cytoskeleton mediates receptor cross talk: An emerging concept in tuning receptor signaling." Journal of Cell Biology 212, no. 3 (February 1, 2016): 267–80. http://dx.doi.org/10.1083/jcb.201504137.
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Recent evidence implicates the actin cytoskeleton in the control of receptor signaling. This may be of particular importance in the context of immune receptors, such as the B cell receptor, where dysregulated signaling can result in autoimmunity and malignancy. Here, we discuss the role of the actin cytoskeleton in controlling receptor compartmentalization, dynamics, and clustering as a means to regulate receptor signaling through controlling the interactions with protein partners. We propose that the actin cytoskeleton is a point of integration for receptor cross talk through modulation of protein dynamics and clustering. We discuss the implication of this cross talk via the cytoskeleton for both ligand-induced and low-level constitutive (tonic) signaling necessary for immune cell survival.
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Strege, Peter R., Adrian N. Holm, Adam Rich, Steven M. Miller, Yijun Ou, Michael G. Sarr, and Gianrico Farrugia. "Cytoskeletal modulation of sodium current in human jejunal circular smooth muscle cells." American Journal of Physiology-Cell Physiology 284, no. 1 (January 1, 2003): C60—C66. http://dx.doi.org/10.1152/ajpcell.00532.2001.
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A Na+ current is present in human jejunal circular smooth muscle cells. The aim of the present study was to determine the role of the cytoskeleton in the regulation of the Na+ current. Whole cell currents were recorded by using standard patch-clamp techniques with Cs+ in the pipette to block K+currents. Cytochalasin D and gelsolin were used to disrupt the actin cytoskeleton and phalloidin to stabilize it. Colchicine was used to disassemble the microtubule cytoskeleton (and intermediate filaments) and paclitaxel to stabilize it. Acrylamide was used to disrupt the intermediate filament cytoskeleton. Perfusion of the recording chamber at 10 ml/min increased peak Na+ current recorded from jejunal smooth muscle cells by 27 ± 3%. Cytochalasin D and gelsolin abolished the perfusion-induced increase in Na+current, whereas incubation with phalloidin, colchicine, paclitaxel, or acrylamide had no effect. In conclusion, the Na+ current expressed in human jejunal circular smooth muscle cells appears to be regulated by the cytoskeleton. An intact actin cytoskeleton is required for perfusion-induced activation of the Na+ current.
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Wang, W. H., A. Cassola, and G. Giebisch. "Involvement of actin cytoskeleton in modulation of apical K channel activity in rat collecting duct." American Journal of Physiology-Renal Physiology 267, no. 4 (October 1, 1994): F592—F598. http://dx.doi.org/10.1152/ajprenal.1994.267.4.f592.
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We have employed the patch-clamp technique to investigate the role of the actin cytoskeleton in the modulation of the low-conductance K+ channel in the apical membrane of the rat cortical collecting duct (CCD). This K+ channel is inactivated by application of cytochalasin B or D, both compounds known to disrupt actin filaments. The effect of both cytochalasins, B and D, was fully reversible in cell-attached patches, but channel activity could not be fully restored in excised membrane patches. The effect of cytochalasins on channel activity was specific and resulted from depolymerization of the actin cytoskeleton, since application of 10 microM chaetoglobosin C, a cytochalasin analogue that does not depolymerize the actin filaments, had no effect on channel activity in inside-out patches. Addition of either actin monomers or of the polymerizing actin filaments in inside-out patches to the cytosolic medium had no effect on channel activity. This suggests that cytochalasin B- or D-induced inactivation of apical K+ channels is not caused by obstruction of the channel pore by actin. We also observed that channel inhibition by cytochalasin B or D could be blocked by pretreatment with 5 microM phalloidin, a compound that stabilizes actin filaments. We conclude that apical K+ channel activity depends critically on the integrity of the actin cytoskeleton.
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Diebel, Lawrence N., David M. Liberati, Manmit S. Saini, Scott A. Dulchavsky, Clement A. Diglio, and William J. Brown. "Actin Mediates Secretory Immunoglobulin a Transport: Effect of Ethanol." American Surgeon 68, no. 9 (September 2002): 769–75. http://dx.doi.org/10.1177/000313480206800907.
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Secretory immunoglobulin A (IgA) is the principle antibody protecting against pathogens at mucosal sites. Ethanol (EtOH) exposure is related to adverse effects on the enterocyte cytoskeleton. The aim of this study was to assess the role of normal cytoskeletal function on IgA transcytosis and its modulation by EtOH by studying Madin-Darby canine kidney (MDCK) cells transfected with the polyimmunoglobulin receptor. MDCK cells were grown as confluent monolayers and treated with 5 per cent EtOH, cytochalasin D (Cyto-D, a cytoskeletal destabilizer), or pretreatment with prostaglandin E2 (a cytoskeletal stabilizer) followed by EtOH. Media alone served as control. IgA was then added to the basolateral side of the chambers, and apical samples were taken for enzyme-linked immunosorbent assay analysis at 0, 3, and 12 hours. Dimeric IgA transcytosis increased in all groups and was significantly depressed by 5 per cent EtOH and Cyto-D. Morphological slides revealed aggregation of actin after Cyto-D treatment. Prostaglandin E2 prevented the decrease in IgA transcytosis seen otherwise with 5 per cent EtOH treatment. We conclude that IgA transcytosis is dependent on actin microfilaments of the cytoskeleton. Decreased IgA transport may lead to mucosal immunodeficiency and infectious complications after EtOH exposure.
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Zheng, Q., Y. Liu, HJ Zhou, YT Du, BP Zhang, J. Zhang, GY Miao, B. Liu, and H. Zhang. "X-ray radiation promotes the metastatic potential of tongue squamous cell carcinoma cells via modulation of biomechanical and cytoskeletal properties." Human & Experimental Toxicology 34, no. 9 (January 13, 2015): 894–903. http://dx.doi.org/10.1177/0960327114561664.
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This study investigated the metastatic potential of tongue squamous cell carcinoma (TSCC) cells after X-ray irradiation as well as radiation-induced changes in the biomechanical properties and cytoskeletal structure that are relevant to metastasis. Tca-8113 TSCC cells were X-ray-irradiated at increasing doses (0, 1, 2, or 4 Gy), and 24 h later, migration was evaluated with the wound healing and transwell migration assays, while invasion was assessed with the Matrigel invasion assay. Confocal and atomic force microscopy were used to examine changes in the structure of the actin cytoskeleton and Young’s modulus (cell stiffness), respectively. X-ray radiation induced dose-dependent increases in invasive and migratory potentials of cells relative to unirradiated control cells ( p < 0.05). The Young’s modulus of irradiated cells was decreased by radiation exposure ( p < 0.05), which was accompanied by alterations in the integrity and organization of the cytoskeletal network, as evidenced by a decrease in the signal intensity of actin fibers ( p < 0.05). X-ray irradiation enhanced migration and invasiveness in Tca-8113 TSCC cells by altering their biomechanical properties and the organization of the actin cytoskeleton. A biomechanics-based analysis can provide an additional platform for assessing tumor response to radiation and optimization of cancer therapies.
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Laux, Thorsten, Kiyoko Fukami, Marcus Thelen, Tamara Golub, Dunja Frey, and Pico Caroni. "Gap43, Marcks, and Cap23 Modulate Pi(4,5)p2 at Plasmalemmal Rafts, and Regulate Cell Cortex Actin Dynamics through a Common Mechanism." Journal of Cell Biology 149, no. 7 (June 26, 2000): 1455–72. http://dx.doi.org/10.1083/jcb.149.7.1455.
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The dynamic properties of the cell cortex and its actin cytoskeleton determine important aspects of cell behavior and are a major target of cell regulation. GAP43, myristoylated alanine-rich C kinase substrate (MARCKS), and CAP23 (GMC) are locally abundant, plasmalemma-associated PKC substrates that affect actin cytoskeleton. Their expression correlates with morphogenic processes and cell motility, but their role in cortex regulation has been difficult to define mechanistically. We now show that the three proteins accumulate at rafts, where they codistribute with PI(4,5)P2, and promote its retention and clustering. Binding and modulation of PI(4,5)P2 depended on the basic effector domain (ED) of these proteins, and constructs lacking the ED functioned as dominant inhibitors of plasmalemmal PI(4,5)P2 modulation. In the neuronlike cell line, PC12, NGF- and substrate-induced peripheral actin structures, and neurite outgrowth were greatly augmented by any of the three proteins, and suppressed by ΔED mutants. Agents that globally mask PI(4,5)P2 mimicked the effects of GMC on peripheral actin recruitment and cell spreading, but interfered with polarization and process formation. Dominant negative GAP43(ΔED) also interfered with peripheral nerve regeneration, stimulus-induced nerve sprouting and control of anatomical plasticity at the neuromuscular junction of transgenic mice. These results suggest that GMC are functionally and mechanistically related PI(4,5)P2 modulating proteins, upstream of actin and cell cortex dynamics regulation.
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Yu, Y., A. A. Smoligovets, and J. T. Groves. "Modulation of T cell signaling by the actin cytoskeleton." Journal of Cell Science 126, no. 5 (March 1, 2013): 1049–58. http://dx.doi.org/10.1242/jcs.098210.
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Strauss, Randy E., and Robert G. Gourdie. "Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation." Biomolecules 10, no. 12 (December 10, 2020): 1656. http://dx.doi.org/10.3390/biom10121656.
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Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers. Mounting evidence of crosstalk between connexins, the cytoskeleton, focal adhesion complexes, and junctional structures has led to a growing appreciation of how barrier-modulating mechanisms may work together to effect solute and cellular flux across tissue boundaries. This new understanding could translate into improved therapeutic outcomes in the treatment of barrier-associated diseases.
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Le Moigne, Ronan, Frédéric Subra, Manale Karam, and Christian Auclair. "The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells." Cells 9, no. 5 (May 8, 2020): 1168. http://dx.doi.org/10.3390/cells9051168.
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Numerous studies have shown that alteration of actin remodeling plays a pivotal role in the regulation of morphologic and phenotypic changes leading to malignancy. In the present study, we searched for drugs that can regulate actin polymerization and reverse the malignant phenotype in cancer cells. We developed a cell-free high-throughput screening assay for the identification of compounds that induce the actin polymerization in vitro, by fluorescence anisotropy. Then, the potential of the hit compound to restore the actin cytoskeleton and reverse the malignant phenotype was checked in EWS-Fli1-transformed fibroblasts and in B16-F10 melanoma cells. A β-carboline extracted from Peganum harmala (i.e., harmine) is identified as a stimulator of actin polymerization through a mechanism independent of actin binding and requiring intracellular factors involved in a process that regulates actin kinetics. Treatment of malignant cells with non-cytotoxic concentrations of harmine induces the recovery of a non-malignant cell morphology accompanied by reorganization of the actin cytoskeleton, rescued cell–cell adhesion, inhibition of cell motility and loss of anchorage-independent growth. In conclusion, harmine induces the reversion of the malignant phenotype by a process involving the modulation of actin dynamics and is a potential anti-tumor agent acting principally through a non-cytotoxic process.
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Wojciak-Stothard, Beata, Belen Torondel, Lan Zhao, Thomas Renné, and James M. Leiper. "Modulation of Rac1 Activity by ADMA/DDAH Regulates Pulmonary Endothelial Barrier Function." Molecular Biology of the Cell 20, no. 1 (January 2009): 33–42. http://dx.doi.org/10.1091/mbc.e08-04-0395.
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Endogenously produced nitric oxide synthase inhibitor, asymmetric methylarginine (ADMA) is associated with vascular dysfunction and endothelial leakage. We studied the role of ADMA, and the enzymes metabolizing it, dimethylarginine dimethylaminohydrolases (DDAH) in the regulation of endothelial barrier function in pulmonary macrovascular and microvascular cells in vitro and in lungs of genetically modified heterozygous DDAHI knockout mice in vivo. We show that ADMA increases pulmonary endothelial permeability in vitro and in in vivo and that this effect is mediated by nitric oxide (NO) acting via protein kinase G (PKG) and independent of reactive oxygen species formation. ADMA-induced remodeling of actin cytoskeleton and intercellular adherens junctions results from a decrease in PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and a subsequent down-regulation of Rac1 activity. The effects of ADMA on endothelial permeability, Rac1 activation and VASP phosphorylation are prevented by overexpression of active DDAHI and DDAHII, whereas inactive DDAH mutants have no effect. These findings demonstrate for the first time that ADMA metabolism critically determines pulmonary endothelial barrier function by modulating Rac1-mediated remodeling of the actin cytoskeleton and intercellular junctions.
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Woodring, Pamela J., E. David Litwack, Dennis D. M. O'Leary, Ginger R. Lucero, Jean Y. J. Wang, and Tony Hunter. "Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension." Journal of Cell Biology 156, no. 5 (February 25, 2002): 879–92. http://dx.doi.org/10.1083/jcb.200110014.
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The nonreceptor tyrosine kinase encoded by the c-Abl gene has the unique feature of an F-actin binding domain (FABD). Purified c-Abl tyrosine kinase is inhibited by F-actin, and this inhibition can be relieved through mutation of its FABD. The c-Abl kinase is activated by physiological signals that also regulate the actin cytoskeleton. We show here that c-Abl stimulated the formation of actin microspikes in fibroblasts spreading on fibronectin. This function of c-Abl is dependent on kinase activity and is not shared by c-Src tyrosine kinase. The Abl-dependent F-actin microspikes occurred under conditions where the Rho-family GTPases were inhibited. The FABD-mutated c-Abl, which is active in detached fibroblasts, stimulated F-actin microspikes independent of cell attachment. Moreover, FABD-mutated c-Abl stimulated the formation of F-actin branches in neurites of rat embryonic cortical neurons. The reciprocal regulation between F-actin and the c-Abl tyrosine kinase may provide a self-limiting mechanism in the control of actin cytoskeleton dynamics.
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Azevedo, Elisama, Leandro Teixeira Oliveira, Ana Karina Castro Lima, Rodrigo Terra, Patrícia Maria Lourenço Dutra, and Verônica P. Salerno. "Interactions betweenLeishmania braziliensisand Macrophages Are Dependent on the Cytoskeleton and Myosin Va." Journal of Parasitology Research 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/275436.
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Leishmaniasis is a neglected tropical disease with no effective vaccines. Actin, microtubules and the actin-based molecular motor myosin Va were investigated for their involvement inLeishmania braziliensismacrophage interactions. Results showed a decrease in the association index when macrophages were without F-actin or microtubules regardless of the activation state of the macrophage. In the absence of F-actin, the production of NO in non-activated cells increased, while in activated cells, the production of NO was reduced independent of parasites. The opposite effect of an increased NO production was observed in the absence of microtubules. In activated cells, the loss of cytoskeletal components inhibited the release of IL-10 during parasite interactions. The production of IL-10 also decreased in the absence of actin or microtubules in non-activated macrophages. Only the disruption of actin altered the production of TNF-αin activated macrophages. The expression of myosin Va tail resulted in an acute decrease in the association index between transfected macrophages andL. braziliensispromastigotes. These data reveal the importance of F-actin, microtubules, and myosin-Va suggesting that modulation of the cytoskeleton may be a mechanism used byL. braziliensisto overcome the natural responses of macrophages to establish infections.
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Imamura, Yuzo, Masahiko Itoh, Yoshito Maeno, Shoichiro Tsukita, and Akira Nagafuchi. "Functional Domains of α-Catenin Required for the Strong State of Cadherin-based Cell Adhesion." Journal of Cell Biology 144, no. 6 (March 22, 1999): 1311–22. http://dx.doi.org/10.1083/jcb.144.6.1311.
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The interaction of cadherin–catenin complex with the actin-based cytoskeleton through α-catenin is indispensable for cadherin-based cell adhesion activity. We reported previously that E-cadherin–α-catenin fusion molecules showed cell adhesion and cytoskeleton binding activities when expressed in nonepithelial L cells. Here, we constructed deletion mutants of E-cadherin–α-catenin fusion molecules lacking various domains of α-catenin and introduced them into L cells. Detailed analysis identified three distinct functional domains of α-catenin: a vinculin/α-actinin-binding domain, a ZO-1-binding domain, and an adhesion-modulation domain. Furthermore, cell dissociation assay revealed that the fusion molecules containing the ZO-1-binding domain in addition to the adhesion-modulation domain conferred the strong state of cell adhesion activity on transfectants, although those lacking the ZO-1-binding domain conferred only the weak state. The disorganization of actin-based cytoskeleton by cytochalasin D treatment shifted the cadherin-based cell adhesion from the strong to the weak state. In the epithelial cells, where α-catenin was not precisely colocalized with ZO-1, the ZO-1-binding domain did not completely support the strong state of cell adhesion activity. Our studies showed that the interaction of α-catenin with the actin-based cytoskeleton through the ZO-1-binding domain is required for the strong state of E-cadherin–based cell adhesion activity.
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Gill, Ravinder K., Le Shen, Jerrold R. Turner, Seema Saksena, Waddah A. Alrefai, Nitika Pant, Ali Esmaili, Alka Dwivedi, Krishnamurthy Ramaswamy, and Pradeep K. Dudeja. "Serotonin modifies cytoskeleton and brush-border membrane architecture in human intestinal epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 4 (October 2008): G700—G708. http://dx.doi.org/10.1152/ajpgi.90362.2008.
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Serotonin or 5-hydroxytryptamine (5-HT) influences numerous functions in the gastrointestinal tract. We previously demonstrated that 5-HT treatment of Caco-2 cells inhibited Na+/H+ exchangers (NHE) and Cl−/OH− exchange activities via distinct signaling mechanisms. Since regulation of several ion transporters such as NHE3 is influenced by intact cytoskeleton, we hypothesized that 5-HT modifies actin cytoskeleton and/or brush-border membrane architecture via involvement of signaling pathways. Ultrastructural analysis showed that 5-HT (0.1 μM, 1 h) treatment of Caco-2 cells caused the apical membrane to assume a convex dome shape that was associated with shortening of microvilli. To examine whether these cellular architecture changes are cytoskeleton driven, we analyzed actin cytoskeleton by fluorescence microscopy. 5-HT induced basal stress fibers with prominent cortical actin filaments via 5-HT3 and 5-HT4 receptor subtypes. This induction was partially attenuated by chelation of intracellular Ca2+ and PKCα inhibition (Go6976). In vitro assays revealed that PKCα interacted with actin and this association was increased by 5-HT. Our data provide novel evidence that 5-HT-induced signaling via 5-HT3/4 receptor subtypes to cause Ca2+ and PKCα-dependent regulation of actin cytoskeleton may play an important role in modulation of ion transporters that contribute to pathophysiology of diarrheal conditions associated with elevated levels of 5-HT.
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Galan, J. E., and D. Zhou. "Striking a balance: Modulation of the actin cytoskeleton by Salmonella." Proceedings of the National Academy of Sciences 97, no. 16 (August 1, 2000): 8754–61. http://dx.doi.org/10.1073/pnas.97.16.8754.
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Azevedo, Maria M., Helena S. Domingues, Fabrice P. Cordelières, Paula Sampaio, Ana I. Seixas, and João B. Relvas. "Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics." Glia 66, no. 9 (May 6, 2018): 1826–44. http://dx.doi.org/10.1002/glia.23342.
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Janson, L. W., J. Kolega, and D. L. Taylor. "Modulation of contraction by gelation/solation in a reconstituted motile model." Journal of Cell Biology 114, no. 5 (September 1, 1991): 1005–15. http://dx.doi.org/10.1083/jcb.114.5.1005.
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The actin-based cytoskeleton is a dynamic component of living cells with major structural and contractile properties involved in fundamental cellular processes. The action of actin-binding proteins can decrease or increase the gel structure. Changes in the actin-based cytoskeleton have long been thought to modulate the myosin II-based contractions involved in these cellular processes, but there has been some debate concerning whether maximal gelation increases or decreases contractile activity. To address this question, we have examined how contractile activity is modulated by the extent of actin gelation. The model system consists of physiologically relevant concentrations and molar ratios of actin filaments (whose lengths are controlled by gelsolin), the actin-cross-linking protein filamin, and smooth muscle myosin II. This system has been studied at the macroscopic and light microscopic levels to relate the gel structure to the rate of contraction. We present results which show that while a minimal amount of structure is necessary to transmit the contractile force, increasing the gel structure inhibits the rate of contraction, despite an increase in the actin-activated Mg(2+)-ATPase activity of myosin. Decreasing the total myosin concentration also inhibits the rate of contraction. Application of cytochalasin D to one side of the contractile network increases the rate of contraction and also induces movement comparable to flare streaming observed in isolated amoeba cytoplasm. These results are interpreted relative to current models of the relationship between the state of gelation and contraction and to the potential effects of such a relationship in the living cell.
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Caven, Liam, and Rey A. Carabeo. "Pathogenic Puppetry: Manipulation of the Host Actin Cytoskeleton by Chlamydia trachomatis." International Journal of Molecular Sciences 21, no. 1 (December 21, 2019): 90. http://dx.doi.org/10.3390/ijms21010090.
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The actin cytoskeleton is crucially important to maintenance of the cellular structure, cell motility, and endocytosis. Accordingly, bacterial pathogens often co-opt the actin-restructuring machinery of host cells to access or create a favorable environment for their own replication. The obligate intracellular organism Chlamydia trachomatis and related species exemplify this dynamic: by inducing actin polymerization at the site of pathogen-host attachment, Chlamydiae induce their own uptake by the typically non-phagocytic epithelium they infect. The interaction of chlamydial adhesins with host surface receptors has been implicated in this effect, as has the activity of the chlamydial effector TarP (translocated actin recruitment protein). Following invasion, C. trachomatis dynamically assembles and maintains an actin-rich cage around the pathogen’s membrane-bound replicative niche, known as the chlamydial inclusion. Through further induction of actin polymerization and modulation of the actin-crosslinking protein myosin II, C. trachomatis promotes egress from the host via extrusion of the inclusion. In this review, we present the experimental findings that can inform our understanding of actin-dependent chlamydial pathogenesis, discuss lingering questions, and identify potential avenues of future study.
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Chamlali, Mohamed, Sana Kouba, Lise Rodat-Despoix, Luca Matteo Todesca, Zoltán Pethö, Albrecht Schwab, and Halima Ouadid-Ahidouch. "Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms." Cells 10, no. 12 (December 10, 2021): 3487. http://dx.doi.org/10.3390/cells10123487.
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Orai3 calcium (Ca2+) channels are implicated in multiple breast cancer processes, such as proliferation and survival as well as resistance to chemotherapy. However, their involvement in the breast cancer cell migration processes remains vague. In the present study, we exploited MDA-MB-231 and MDA-MB-231 BrM2 basal-like estrogen receptor-negative (ER−) cell lines to assess the direct role of Orai3 in cell migration. We showed that Orai3 regulates MDA-MB-231 and MDA-MB-231 BrM2 cell migration in two distinct ways. First, we showed that Orai3 remodels cell adhesive capacities by modulating the intracellular Ca2+ concentration. Orai3 silencing (siOrai3) decreased calpain activity, cell adhesion and migration in a Ca2+-dependent manner. In addition, Orai3 interacts with focal adhesion kinase (FAK) and regulates the actin cytoskeleton, in a Ca2+-independent way. Thus, siOrai3 modulates cell morphology by altering F-actin polymerization via a loss of interaction between Orai3 and FAK. To summarize, we demonstrated that Orai3 regulates cell migration through a Ca2+-dependent modulation of calpain activity and, in a Ca2+-independent manner, the actin cytoskeleton architecture via FAK.
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Blum, M. S., E. Toninelli, J. M. Anderson, M. S. Balda, J. Zhou, L. O'Donnell, R. Pardi, and J. R. Bender. "Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 1 (July 1, 1997): H286—H294. http://dx.doi.org/10.1152/ajpheart.1997.273.1.h286.
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The tight junction (TJ) is a specialized intercellular structure responsible for the regulation of ionic and macromolecular flux across cell monolayers. Because plasma leakage is believed to occur mainly across the microvasculature, we hypothesized that microvascular endothelial cells (MVEC) may form more intact, regulatable TJ than other endothelial cell (EC) types, allowing further insight into the control of EC permeability. Primary cultures of MVEC monolayers produced transmonolayer electrical resistances (TER) of 120-155 omega.cm2, approximately 10 times that of large-vessel EC. Treatment with tumor necrosis factor and interferon-gamma caused a 50% decrease in the TER and a striking fragmentation of the basal, continuous interendothelial cell zonula occludens-1 protein (ZO-1) distribution determined by immunofluorescence. Fragmentation was inhibited by cytochalasin D, and confocal microscopy demonstrated a colocalization between F actin and ZO-1. These findings suggest that the F actin cytoskeleton plays a central role in endothelial TJ barrier regulation and that dynamic cytoskeletal alterations may primarily control vascular permeability.
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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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Beckley, Samantha Joy, Morgan Campbell Hunter, Sarah Naulikha Kituyi, Ianthe Wingate, Abantika Chakraborty, Kelly Schwarz, Matodzi Portia Makhubu, et al. "STIP1/HOP Regulates the Actin Cytoskeleton through Interactions with Actin and Changes in Actin-Binding Proteins Cofilin and Profilin." International Journal of Molecular Sciences 21, no. 9 (April 30, 2020): 3152. http://dx.doi.org/10.3390/ijms21093152.
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Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
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Cattelino, Anna, Chiara Albertinazzi, Mario Bossi, David R. Critchley, and Ivan de Curtis. "A Cell-free System to Study Regulation of Focal Adhesions and of the Connected Actin Cytoskeleton." Molecular Biology of the Cell 10, no. 2 (February 1999): 373–91. http://dx.doi.org/10.1091/mbc.10.2.373.
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Assembly and modulation of focal adhesions during dynamic adhesive processes are poorly understood. We describe here the use of ventral plasma membranes from adherent fibroblasts to explore mechanisms regulating integrin distribution and function in a system that preserves the integration of these receptors into the plasma membrane. We find that partial disruption of the cellular organization responsible for the maintenance of organized adhesive sites allows modulation of integrin distribution by divalent cations. High Ca2+ concentrations induce quasi-reversible diffusion of β1 integrins out of focal adhesions, whereas low Ca2+ concentrations induce irreversible recruitment of β1 receptors along extracellular matrix fibrils, as shown by immunofluorescence and electron microscopy. Both effects are independent from the presence of actin stress fibers in this system. Experiments with cells expressing truncated β1 receptors show that the cytoplasmic portion of β1 is required for low Ca2+-induced recruitment of the receptors to matrix fibrils. Analysis with function-modulating antibodies indicates that divalent cation-mediated receptor distribution within the membrane correlates with changes in the functional state of the receptors. Moreover, reconstitution experiments show that purified α-actinin colocalizes and redistributes with β1 receptors on ventral plasma membranes depleted of actin, implicating binding of α-actinin to the receptors. Finally, we found that recruitment of exogenous actin is specifically restricted to focal adhesions under conditions in which new actin polymerization is inhibited. Our data show that the described system can be exploited to investigate the mechanisms of integrin function in an experimental setup that permits receptor redistribution. The possibility to uncouple, under cell-free conditions, events involved in focal adhesion and actin cytoskeleton assembly should facilitate the comprehension of the underlying molecular mechanisms.
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Csépányi-Kömi, Roland, Gábor Sirokmány, Miklós Geiszt, and Erzsébet Ligeti. "ARHGAP25, a novel Rac GTPase-activating protein, regulates phagocytosis in human neutrophilic granulocytes." Blood 119, no. 2 (January 12, 2012): 573–82. http://dx.doi.org/10.1182/blood-2010-12-324053.
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Members of the Rac/Rho family of small GTPases play an essential role in phagocytic cells in organization of the actin cytoskeleton and production of toxic oxygen compounds. GTPase-activating proteins (GAPs) decrease the amount of the GTP-bound active form of small GTPases, and contribute to the control of biologic signals. The number of potential Rac/RhoGAPs largely exceeds the number of Rac/Rho GTPases and the expression profile, and their specific role in different cell types is largely unknown. In this study, we report for the first time the properties of full-length ARHGAP25 protein, and show that it is specifically expressed in hematopoietic cells, and acts as a RacGAP both in vitro and in vivo. By silencing and overexpressing the protein in neutrophil model cell lines (PLB-985 and CosPhoxFcγR, respectively) and in primary macrophages, we demonstrate that ARHGAP25 is a negative regulator of phagocytosis acting probably via modulation of the actin cytoskeleton.
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Landry, Jacques, and Jacques Huot. "Modulation of actin dynamics during stress and physiological stimulation by a signaling pathway involving p38 MAP kinase and heat-shock protein 27." Biochemistry and Cell Biology 73, no. 9-10 (September 1, 1995): 703–7. http://dx.doi.org/10.1139/o95-078.
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HSP27, like other proteins of the heat-shock protein family, accumulates to high levels after exposure of cells to a short period of hyperthermia and contributes to the development of a transient state of thermoresistance. In vitro, HSP27 behaves as an actin cap-binding protein and can inhibit actin polymerization. In vivo, the protective function of HSP27 is exerted mainly at the level of the microfilaments and appears as an extension of a normal function of the protein. This function is regulated by phosphorylation in a mitogen- and stress-sensitive signaling pathway involving the newly characterized p38 MAP kinase. The phosphorylation-modulated function of HSP27 can contribute to agonist-induced reorganization of the actin cytoskeleton and, in the case of stress activation, provides an actin-based adaptive response of cells to the new environmental conditions.Key words: actin cytoskeleton, heat-shock protein, HSP27, signal transduction, stress response, mitogen activated protein kinases.
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Mykkänen, Olli-Matti, Mikaela Grönholm, Mikko Rönty, Maciej Lalowski, Paula Salmikangas, Heli Suila, and Olli Carpén. "Characterization of Human Palladin, a Microfilament-associated Protein." Molecular Biology of the Cell 12, no. 10 (October 2001): 3060–73. http://dx.doi.org/10.1091/mbc.12.10.3060.
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Actin-containing microfilaments control cell shape, adhesion, and contraction. In striated muscle, α-actinin and other Z-disk proteins coordinate the organization and functions of actin filaments. In smooth muscle and nonmuscle cells, periodic structures termed dense bodies and dense regions, respectively, are thought to serve functions analogous to Z-discs. We describe here identification and characterization of human palladin, a protein expressed mainly in smooth muscle and nonmuscle and distributed along microfilaments in a periodic manner consistent with dense regions/bodies. Palladin contains three Ig-domains most homologous to the sarcomeric Z-disk protein myotilin. The N terminus includes an FPPPP motif recognized by the Ena-Vasp homology domain 1 domain in Ena/vasodilatator-stimulated phosphoprotein (VASP)/Wiscott-Aldrich syndrome protein (WASP) protein family. Cytoskeletal proteins with FPPPP motif target Ena/VASP/WASP proteins to sites of actin modulation. We identified palladin in a yeast two-hybrid search as an ezrin-associated protein. An interaction between palladin and ezrin was further verified by affinity precipitation and blot overlay assays. The interaction was mediated by the α-helical domain of ezrin and by Ig-domains 2–3 of palladin. Ezrin is typically a component of the cortical cytoskeleton, but in smooth muscle cells it is localized along microfilaments. These cells express palladin abundantly and thus palladin may be involved in the microfilament localization of ezrin. Palladin expression was up-regulated in differentiating dendritic cells (DCs), coinciding with major cytoskeletal and morphological alterations. In immature DCs, palladin localized in actin-containing podosomes and in mature DCs along actin filaments. The regulated expression and localization suggest a role for palladin in the assembly of DC cytoskeleton.
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Bianchi, Francesca, Michele Sommariva, Laura Brigida Cornaghi, Luca Denti, Ambra Nava, Francesca Arnaboldi, Claudia Moscheni, and Nicoletta Gagliano. "Mechanical Cues, E-Cadherin Expression and Cell “Sociality” Are Crucial Crossroads in Determining Pancreatic Ductal Adenocarcinoma Cells Behavior." Cells 11, no. 8 (April 13, 2022): 1318. http://dx.doi.org/10.3390/cells11081318.
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E-cadherin, an epithelial-to-mesenchymal transition (EMT) marker, is coupled to actin cytoskeleton and distributes cell forces acting on cells. Since YAP transduces mechanical signals involving actin cytoskeleton, we aimed to investigate the relationship between YAP and mechanical cues in pancreatic ductal adenocarcinoma (PDAC) cell lines, characterized by different EMT-related phenotypes, cultured in 2D monolayers and 3D spheroids. We observed that the YAP/p-YAP ratio was reduced in HPAC and MIA PaCa-2 cell lines and remained unchanged in BxPC-3 cells when cultured in a 3D setting. CTGF and CYR61 gene expression were down-regulated in all PDAC 3D compared to 2D cultures, without any significant effect following actin cytoskeleton inhibition by Cytochalasin B (CyB) treatment. Moreover, LATS1 mRNA, indicating the activation of the Hippo pathway, was not influenced by CyB and differed in all PDAC cell lines having different EMT-related phenotype but a similar pattern of CTGF and CYR61 expression. Although the role of YAP modulation in response to mechanical cues in cancer cells remains to be completely elucidated, our results suggest that cell arrangement and phenotype can determine variable outcomes to mechanical stimuli in PDAC cells. Moreover, it is possible to speculate that YAP and Hippo pathways may act as parallel and not exclusive inputs that, converging at some points, may impact cell behavior.
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Paluck, Autumn, Jaspreet Osan, Lauren Hollingsworth, Sattya Narayan Talukdar, Ali Al Saegh, and Masfique Mehedi. "Role of ARP2/3 Complex-Driven Actin Polymerization in RSV Infection." Pathogens 11, no. 1 (December 26, 2021): 26. http://dx.doi.org/10.3390/pathogens11010026.
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Respiratory syncytial virus (RSV) is the leading viral agent causing bronchiolitis and pneumonia in children under five years old worldwide. The RSV infection cycle starts with macropinocytosis-based entry into the host airway epithelial cell membrane, followed by virus transcription, replication, assembly, budding, and spread. It is not surprising that the host actin cytoskeleton contributes to different stages of the RSV replication cycle. RSV modulates actin-related protein 2/3 (ARP2/3) complex-driven actin polymerization for a robust filopodia induction on the infected lung epithelial A549 cells, which contributes to the virus’s budding, and cell-to-cell spread. Thus, a comprehensive understanding of RSV-induced cytoskeletal modulation and its role in lung pathobiology may identify novel intervention strategies. This review will focus on the role of the ARP2/3 complex in RSV’s pathogenesis and possible therapeutic targets to the ARP2/3 complex for RSV.
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Legrand-Poels, S., G. Kustermans, F. Bex, E. Kremmer, T. A. Kufer, and J. Piette. "Modulation of Nod2-dependent NF- B signaling by the actin cytoskeleton." Journal of Cell Science 120, no. 7 (April 1, 2007): 1299–310. http://dx.doi.org/10.1242/jcs.03424.
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Rosado, Juan A., Else M. Y. Meijer, Karly Hamulyak, Irena Novakova, Johan W. M. Heemskerk, and Stewart O. Sage. "Fibrinogen binding to the integrin αIIbβ3 modulates store-mediated calcium entry in human platelets." Blood 97, no. 9 (May 1, 2001): 2648–56. http://dx.doi.org/10.1182/blood.v97.9.2648.
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Abstract Effects of the occupation of integrin αIIbβ3 by fibrinogen on Ca++signaling in fura-2–loaded human platelets were investigated. Adding fibrinogen to washed platelet suspensions inhibited increases in cytosolic [Ca++] concentrations ([Ca++]i) evoked by adenosine diphosphate (ADP) and thrombin in a concentration-dependent manner in the presence of external Ca++ but not in the absence of external Ca++ or in the presence of the nonselective cation channel blocker SKF96365, indicating selective inhibition of Ca++entry. Fibrinogen also inhibited store-mediated Ca++ entry (SMCE) activated after Ca++ store depletion using thapsigargin. The inhibitory effect of fibrinogen was reversed if fibrinogen binding to αIIbβ3 was blocked using RDGS or abciximab and was absent in platelets from patients homozygous for Glanzmann thrombasthenia. Fibrinogen was without effect on SMCE once activated. Activation of SMCE in platelets occurs through conformational coupling between the intracellular stores and the plasma membrane and requires remodeling of the actin cytoskeleton. Fibrinogen inhibited actin polymerization evoked by ADP or thapsigargin in control cells and in cells loaded with the Ca++ chelator dimethyl BAPTA. It also inhibited the translocation of the tyrosine kinase p60src to the cytoskeleton. These results indicate that the binding of fibrinogen to integrin αIIbβ3 inhibits the activation of SMCE in platelets by a mechanism that may involve modulation of the reorganization of the actin cytoskeleton and the cytoskeletal association of p60src. This action may be important in intrinsic negative feedback to prevent the further activation of platelets subjected to low-level stimuli in vivo.
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Trichet, Léa, Cécile Sykes, and Julie Plastino. "Relaxing the actin cytoskeleton for adhesion and movement with Ena/VASP." Journal of Cell Biology 181, no. 1 (March 31, 2008): 19–25. http://dx.doi.org/10.1083/jcb.200710168.
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At cell–cell contacts, as well as at the leading edge of motile cells, the plasticity of actin structures is maintained, in part, through labile connections to the plasma membrane. Here we explain how and why Drosophila enabled/vasodilator stimulated phosphoprotein (Ena/VASP) proteins are candidates for driving this cytoskeleton modulation under the membrane.
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Gliem, Martin, Wolfgang-Moritz Heupel, Volker Spindler, Gregory S. Harms, and Jens Waschke. "Actin reorganization contributes to loss of cell adhesion in pemphigus vulgaris." American Journal of Physiology-Cell Physiology 299, no. 3 (September 2010): C606—C613. http://dx.doi.org/10.1152/ajpcell.00075.2010.
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In the human autoimmune blistering skin disease pemphigus vulgaris autoantibodies (PV-IgG), which are mainly directed against keratinocyte cell adhesion molecules desmoglein (Dsg) 3 and Dsg1, cause keratinocyte cell dissociation (acantholysis). Recent studies reported that loss of keratinocyte cell adhesion was accompanied by profound alterations of the actin cytoskeleton. Nevertheless, the relevance of actin reorganization in this process is unclear at present. In this study, we provide evidence for an important role of actin reorganization in pemphigus pathogenesis. In parallel to loss of cell adhesion and fragmentation of Dsg3 staining along cell borders, PV-IgG treatment resulted in striking changes in actin cytoskeleton organization. Moreover, in experiments using fluorescence recovery after photobleaching (FRAP), PV-IgG were detected to interfere with actin dynamics. Therefore, we investigated whether pharmacological manipulation of actin polymerization modulates pathogenic effects of PV-IgG. Pharmacological stabilization of actin filaments via jasplakinolide significantly blocked cell dissociation and Dsg3 fragmentation, whereas cytochalasin D-induced actin depolymerization strongly enhanced pathogenic effects of PV-IgG. To substantiate these findings, we studied whether the protective effects of Rho GTPases, which are potent regulators of the actin cytoskeleton and were shown to be involved in pemphigus pathogenesis, were dependent on modulation of actin dynamics. Cytotoxic necrotizing factor-1 (CNF-1)-mediated activation of Rho-GTPases enhanced the cortical junction-associated actin belt and blunted PV-IgG-induced cell dissociation. However, when actin polymerization was blocked under these conditions via addition of latrunculin B, the protective effects of CNF-1 were abrogated. Taken together, these experiments indicate that reorganization of cortical actin filaments is a critical step in PV-IgG-induced keratinocyte dissociation.
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Yu, Jowie C. H., Samantha M. Lloyd-Burton, Robin F. Irvine, and Michael J. Schell. "Regulation of the localization and activity of inositol 1,4,5-trisphosphate 3-kinase B in intact cells by proteolysis." Biochemical Journal 392, no. 3 (December 6, 2005): 435–41. http://dx.doi.org/10.1042/bj20050829.
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IP3K (inositol 1,4,5-trisphosphate 3-kinase) catalyses the Ca2+-regulated phosphorylation of the second messenger Ins(1,4,5)P3, thereby inactivating the signal to release Ca2+ and generating Ins(1,3,4,5)P4. Here we have investigated the localization and activity of IP3KB and its modulation by proteolysis. We found that the N- and C-termini (either side of residue 262) of IP3KB localized predominantly to the actin cytoskeleton and ER (endoplasmic reticulum) respectively, both in COS-7 cells and in primary astrocytes. The functional relevance of this was demonstrated by showing that full-length (actin-localized) IP3KB abolished the histamine-induced Ca2+ response in HeLa cells more effectively than truncated constructs localized to the ER or cytosol. The superior efficacy of full-length IP3KB was also attenuated by disruption of the actin cytoskeleton. By transfecting COS-7 cells with double-tagged IP3KB, we show that the translocation from actin to ER may be a physiologically regulated process caused by Ca2+-modulated constitutive proteolysis in intact cells.
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Soundararajan, Avinash, Sachin Anil Ghag, Sai Supriya Vuda, Ting Wang, and Padmanabhan Paranji Pattabiraman. "Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway." Cells 10, no. 11 (October 24, 2021): 2864. http://dx.doi.org/10.3390/cells10112864.
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The homeostasis of extracellular matrix (ECM) and actin dynamics in the trabecular meshwork (TM) outflow pathway plays a critical role in intraocular pressure (IOP) regulation. We studied the role of cathepsin K (CTSK), a lysosomal cysteine protease and a potent collagenase, on ECM modulation and actin cytoskeleton rearrangements in the TM outflow pathway and the regulation of IOP. Initially, we found that CTSK was negatively regulated by pathological stressors known to elevate IOP. Further, inactivating CTSK using balicatib, a pharmacological cell-permeable inhibitor of CTSK, resulted in IOP elevation due to increased levels and excessive deposition of ECM-like collagen-1A in the TM outflow pathway. The loss of CTSK activity resulted in actin-bundling via fascin and vinculin reorganization and by inhibiting actin depolymerization via phospho-cofilin. Contrarily, constitutive expression of CTSK decreased ECM and increased actin depolymerization by decreasing phospho-cofilin, negatively regulated the availability of active TGFβ2, and reduced the levels of alpha-smooth muscle actin (αSMA), indicating an antifibrotic action of CTSK. In conclusion, these observations, for the first time, demonstrate the significance of CTSK in IOP regulation by maintaining the ECM homeostasis and actin cytoskeleton-mediated contractile properties of the TM outflow pathway.
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Peng, Ching-Tien, and Kang-Hsi Wu. "Identification of Phenotypic Modulation of Angiotensin-(1-7) in Thrombin-Stimulated Human Aortic Endothelial Cells from iTRAQ Quantitative Proteomics." Blood 128, no. 22 (December 2, 2016): 4999. http://dx.doi.org/10.1182/blood.v128.22.4999.4999.
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Abstract Introduction: The primary effector of renin-angiotensin system (RAS) system is angiotensin II. RAS activation causes many detrimental effects via AT1 receptor. Angiotensin-(1-7)/ angiotensin-converting enzyme 2/Mas axis is a newly identified counter-regulatory pathway against RAS system. Thrombin plays a critical role in coagulation and inflammation processes in vascular endothelium. Although RAS activation is associated with thrombotic complications, it is unknown whether angiotensin-(1-7) can modulate the pleotropic effects of thrombin. In this study, we investigate the proteomic changes of angiotensin-(1-7) effects on thrombin-stimulated human aortic endothelial cells (HAECs). Materials and methods: HAECs were pretreated with 10-7M anigotenion-(1-7) for 1 h and stimulated with 2 units/mL thrombin for additional 5 h. Their proteomes were investigated using isobaric tags for the relative and absolute quantification (iTRAQ) and MetaCoreTMsoftware. Results: A total of 653, 717 and 801 proteins were identified in triplicated iTRAQ analyses. MetaCoreTM pathway analysis identified that iTRAQ data showed the consistent pathway alterations (70%) in triplicated experiments. The same altered pathways included "Cytoskeleton remodeling_Cytoskeleton remodeling", "Cell adhesion_Integrin-mediated cell adhesion and migration", "Cell adhesion_Chemokines and adhesion" , "Cytoskeleton remodeling _ Regulation of actin cytoskeleton by Rho GTPases", "LRRK2 in neurons in Parkinson's disease", "Cytoskeleton remodeling_Fibronectin-binding integrins in cell motility", "Cytoskeleton remodeling _TGF, WNT and cytoskeletal remodeling" were among the top 10 statistically significant pathways. Additional experiments validated the phenotypes of angiotensin-(1-7) effects in thrombin-stimulated HAECs. Conclusions: Several regulatory pathways are altered by angiotensin-(1-7) in thrombin-stimulated HAECs, with cytoskeleton remodeling, cell adhesion and cell migration (motility) as the dominant altered phenotypes. Disclosures No relevant conflicts of interest to declare.
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Howard, Andrew, and Arthur Alberts. "Rescuing cancer immunity through formins and the actin cytoskeleton (VAC3P.1063)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 71.10. http://dx.doi.org/10.4049/jimmunol.194.supp.71.10.
Full textAbstract:
Abstract Immunotherapy strives to replace radiation, chemo and surgery in the fight against cancer by reversing cancer’s suppression of the immune system. CTLA-4 and PDL1 checkpoint blockade inhibitors are emerging therapies that release anti-tumor T cells to kill the tumor. However, cancer also alters myeloid activation to systemically suppress the immune system, which may explain the range of responses to checkpoint blockade inhibitors. We strive to better understand myeloid activation in cancer and develop therapies to modulate these altered responses. Through in vitro myeloid activation assays, we investigated the mechanism of action for two established immunomodulatory compounds, lenalidomide and tipifarnib, as well as tested novel small molecule Intramimics, developed by our lab, for immunomodulatory function. We found that lenalidomide and tipifarnib modulate immune responses through their activation of Rho GTPases and their downstream effectors to promote F-actin assembly. Interestingly, Intramimics prove to be better at modulating immune responses as they directly activate the diaphanous related formin effectors of Rho GTPases. We propose that modulation occurs mechanistically through the MADS box transcription factor SRF, which senses actin dynamics within the cell. We intend to confirm the dependency of SRF in immunomodulation and test these therapeutics in combination with checkpoint blockade inhibitors in preclinical cancer models in the future.
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Ebata, Takahiro, Hiroaki Hirata, and Keiko Kawauchi. "Functions of the Tumor Suppressors p53 and Rb in Actin Cytoskeleton Remodeling." BioMed Research International 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/9231057.
Full textAbstract:
Mechanical microenvironments, such as extracellular matrix stiffness and strain, have crucial roles in cancer progression. Cells sense their microenvironments with mechanosensing biomolecules, which is accompanied by the modulation of actin cytoskeleton structures, and the signals are subsequently transduced downstream as biochemical signals. The tumor suppressors p53 and retinoblastoma protein (Rb) are known to prevent cancer progression. The p53 and Rb signaling pathways are disrupted in many types of cancers. Here, we review recent findings about the roles of these tumor suppressors in the regulation of mechanosensing biomolecules and the actin cytoskeleton. We further discuss how dysfunction in the p53- and/or Rb-mediated mechanosignaling pathways is potentially involved in cancer progression. These pathways might provide good targets for developing anticancer therapies.
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Scaife, Robin M., Didier Job, and Wallace Y. Langdon. "Rapid Microtubule-dependent Induction of Neurite-like Extensions in NIH 3T3 Fibroblasts by Inhibition of ROCK and Cbl." Molecular Biology of the Cell 14, no. 11 (November 2003): 4605–17. http://dx.doi.org/10.1091/mbc.e02-11-0739.
Full textAbstract:
A number of key cellular functions, such as morphological differentiation and cell motility, are closely associated with changes in cytoskeletal dynamics. Many of the principal signaling components involved in actin cytoskeletal dynamics have been identified, and these have been shown to be critically involved in cell motility. In contrast, signaling to microtubules remains relatively uncharacterized, and the importance of signaling pathways in modulation of microtubule dynamics has so far not been established clearly. We report here that the Rho-effector ROCK and the multiadaptor proto-oncoprotein Cbl can profoundly affect the microtubule cytoskeleton. Simultaneous inhibition of these two signaling molecules induces a dramatic rearrangement of the microtubule cytoskeleton into microtubule bundles. The formation of these microtubule bundles, which does not involve signaling by Rac, Cdc42, Crk, phosphatidylinositol 3-kinase, and Abl, is sufficient to induce distinct neurite-like extensions in NIH 3T3 fibroblasts, even in the absence of microfilaments. This novel microtubule-dependent function that promotes neurite-like extensions is not dependent on net changes in microtubule polymerization or stabilization, but rather involves selective elongation and reorganization of microtubules into long bundles.
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Gatfield, John, Imke Albrecht, Bettina Zanolari, Michel O. Steinmetz, and Jean Pieters. "Association of the Leukocyte Plasma Membrane with the Actin Cytoskeleton through Coiled Coil-mediated Trimeric Coronin 1 Molecules." Molecular Biology of the Cell 16, no. 6 (June 2005): 2786–98. http://dx.doi.org/10.1091/mbc.e05-01-0042.
Full textAbstract:
Coronin 1 is a member of the coronin protein family specifically expressed in leukocytes and accumulates at sites of rearrangements of the F-actin cytoskeleton. Here, we describe that coronin 1 molecules are coiled coil-mediated homotrimeric complexes, which associate with the plasma membrane and with the cytoskeleton via two distinct domains. Association with the cytoskeleton was mediated by trimerization of a stretch of positively charged residues within a linker region between the N-terminal, WD repeat-containing domain and the C-terminal coiled coil. In contrast, neither the coiled coil nor the positively charged residues within the linker domain were required for plasma membrane binding, suggesting that the N-terminal, WD repeat-containing domain mediates membrane interaction. The capacity of coronin 1 to link the leukocyte cytoskeleton to the plasma membrane may serve to integrate outside-inside signaling with modulation of the cytoskeleton.