Academic literature on the topic 'FAK, microtubule'
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Journal articles on the topic "FAK, microtubule"
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Li, Xiao-Yan, Xiaoming Zhou, R. Grant Rowe, Yuexian Hu, David D. Schlaepfer, Dusko Ilić, Gregory Dressler, Ann Park, Jun-Lin Guan, and Stephen J. Weiss. "Snail1 controls epithelial–mesenchymal lineage commitment in focal adhesion kinase–null embryonic cells." Journal of Cell Biology 195, no. 5 (November 21, 2011): 729–38. http://dx.doi.org/10.1083/jcb.201105103.
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Mouse embryonic cells isolated from focal adhesion kinase (FAK)–null animals at embryonic day 7.5 display multiple defects in focal adhesion remodeling, microtubule dynamics, mechanotransduction, proliferation, directional motility, and invasion. To date, the ability of FAK to modulate cell function has been ascribed largely to its control of posttranscriptional signaling cascades in this embryonic cell population. In this paper, we demonstrate that FAK unexpectedly exerts control over an epithelial–mesenchymal transition (EMT) program that commits embryonic FAK-null cells to an epithelial status highlighted by the expression of E-cadherin, desmoplakin, and cytokeratins. FAK rescue reestablished the mesenchymal characteristics of FAK-null embryonic cells to generate committed mouse embryonic fibroblasts via an extracellular signal–related kinase– and Akt-dependent signaling cascade that triggered Snail1 gene expression and Snail1 protein stabilization. These findings indentify FAK as a novel regulator of Snail1-dependent EMT in embryonic cells and suggest that multiple defects in FAK−/− cell behavior can be attributed to an inappropriate commitment of these cells to an epithelial, rather than fibroblastic, phenotype.
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Yilmaz, Özlem, Patrick A. Young, Richard J. Lamont, and George E. Kenny. "Gingival epithelial cell signalling and cytoskeletal responses to Porphyromonas gingivalis invasion." Microbiology 149, no. 9 (September 1, 2003): 2417–26. http://dx.doi.org/10.1099/mic.0.26483-0.
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Porphyromonas gingivalis, an oral pathogen, can internalize within primary gingival epithelial cells (GECs) through an invasion mechanism mediated by interactions between P. gingivalis fimbriae and integrins on the surface of the GECs. Fimbriae–integrin-based signalling events were studied by fluorescence microscopy, and the subcellular localization of integrin-associated signalling molecules paxillin and focal adhesion kinase (FAK), and the architecture of the actin and microtubule cytoskeleton were examined. GECs infected with P. gingivalis for 30 min demonstrated significant redistribution of paxillin and FAK from the cytosol to cell peripheries and assembly into focal adhesion complexes. In contrast, a fimbriae-deficient mutant of P. gingivalis did not contribute substantially to activation of paxillin or FAK. After 24 h, the majority of paxillin and FAK had returned to the cytoplasm with significant co-localization with P. gingivalis in the perinuclear region. Wild-type P. gingivalis induced nucleation of actin filaments forming microspike-like protrusions and long stable microfilaments distributed throughout the cells. Fimbriae mutants promoted a rich cortical actin meshwork accompanied by membrane ruffling dispersed along the cell membrane. Remarkable disassembly and nucleation of the actin and microtubule filamentous network was observed following 24 h infection with either wild-type or fimbriae-deficient mutants of P. gingivalis. The results show that fimbriated P. gingivalis cells induce formation of integrin-associated focal adhesions with subsequent remodelling of the actin and tubulin cytoskeleton.
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Paradžik, Tina, Iva I. Podgorski, Tanja Vojvoda Zeljko, and Mladen Paradžik. "Ancient Origins of Cytoskeletal Crosstalk: Spectraplakin-like Proteins Precede the Emergence of Cortical Microtubule Stabilization Complexes as Crosslinkers." International Journal of Molecular Sciences 23, no. 10 (May 17, 2022): 5594. http://dx.doi.org/10.3390/ijms23105594.
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Adhesion between cells and the extracellular matrix (ECM) is one of the prerequisites for multicellularity, motility, and tissue specialization. Focal adhesions (FAs) are defined as protein complexes that mediate signals from the ECM to major components of the cytoskeleton (microtubules, actin, and intermediate filaments), and their mutual communication determines a variety of cellular processes. In this study, human cytoskeletal crosstalk proteins were identified by comparing datasets with experimentally determined cytoskeletal proteins. The spectraplakin dystonin was the only protein found in all datasets. Other proteins (FAK, RAC1, septin 9, MISP, and ezrin) were detected at the intersections of FAs, microtubules, and actin cytoskeleton. Homology searches for human crosstalk proteins as queries were performed against a predefined dataset of proteomes. This analysis highlighted the importance of FA communication with the actin and microtubule cytoskeleton, as these crosstalk proteins exhibit the highest degree of evolutionary conservation. Finally, phylogenetic analyses elucidated the early evolutionary history of spectraplakins and cortical microtubule stabilization complexes (CMSCs) as model representatives of the human cytoskeletal crosstalk. While spectraplakins probably arose at the onset of opisthokont evolution, the crosstalk between FAs and microtubules is associated with the emergence of metazoans. The multiprotein complexes contributing to cytoskeletal crosstalk in animals gradually gained in complexity from the onset of metazoan evolution.
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Dubois, Fatemeh, Kyle Alpha, and Christopher E. Turner. "Paxillin regulates cell polarization and anterograde vesicle trafficking during cell migration." Molecular Biology of the Cell 28, no. 26 (December 15, 2017): 3815–31. http://dx.doi.org/10.1091/mbc.e17-08-0488.
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Cell polarization and directed migration play pivotal roles in diverse physiological and pathological processes. Herein, we identify new roles for paxillin-mediated HDAC6 inhibition in regulating key aspects of cell polarization in both two-dimensional and one-dimensional matrix environments. Paxillin, by modulating microtubule acetylation through HDAC6 regulation, was shown to control centrosome and Golgi reorientation toward the leading edge, a hallmark of cell polarization to ensure directed trafficking of promigratory factors. Paxillin was also required for pericentrosomal Golgi localization and centrosome cohesion, independent of its localization to, and role in, focal adhesion signaling. In addition, we provide evidence of an accumulation of paxillin at the centrosome that is dependent on focal adhesion kinase (FAK) and identify an important collaboration between paxillin and FAK signaling in the modulation of microtubule acetylation, as well as centrosome and Golgi organization and polarization. Finally, paxillin was also shown to be required for optimal anterograde vesicular trafficking to the plasma membrane.
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Chanez, Brice, Kevin Ostacolo, Ali Badache, and Sylvie Thuault. "EB1 Restricts Breast Cancer Cell Invadopodia Formation and Matrix Proteolysis via FAK." Cells 10, no. 2 (February 13, 2021): 388. http://dx.doi.org/10.3390/cells10020388.
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Regulation of microtubule dynamics by plus-end tracking proteins (+TIPs) plays an essential role in cancer cell migration. However, the role of +TIPs in cancer cell invasion has been poorly addressed. Invadopodia, actin-rich protrusions specialized in extracellular matrix degradation, are essential for cancer cell invasion and metastasis, the leading cause of death in breast cancer. We, therefore, investigated the role of the End Binding protein, EB1, a major hub of the +TIP network, in invadopodia functions. EB1 silencing increased matrix degradation by breast cancer cells. This was recapitulated by depletion of two additional +TIPs and EB1 partners, APC and ACF7, but not by the knockdown of other +TIPs, such as CLASP1/2 or CLIP170. The knockdown of Focal Adhesion Kinase (FAK) was previously proposed to similarly promote invadopodia formation as a consequence of a switch of the Src kinase from focal adhesions to invadopodia. Interestingly, EB1-, APC-, or ACF7-depleted cells had decreased expression/activation of FAK. Remarkably, overexpression of wild type FAK, but not of FAK mutated to prevent Src recruitment, prevented the increased degradative activity induced by EB1 depletion. Overall, we propose that EB1 restricts invadopodia formation through the control of FAK and, consequently, the spatial regulation of Src activity.
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Fortin, Jessica S., Alexandre Patenaude, Rena G. Deschesnes, Marie-France Côté, Eric Petitclerc, and René C.-Gaudreault. "ASK1-P38 Pathway is Important for Anoikis Induced by Microtubule-Targeting Aryl Chloroethylureas." Journal of Pharmacy & Pharmaceutical Sciences 13, no. 2 (June 7, 2010): 175. http://dx.doi.org/10.18433/j31g6c.
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PURPOSE. We investigated the involvement of MAPK signaling in the cell death mechanisms of classical microtubule interfering agents (MIA) and aryl-3-(2-chloroethyl)ureas (CEU) acting as antimitotics, along with CEU that don’t affect directly microtubules (non-MIA CEU). METHODS.
To ascertain the activated signaling pathway profile of MIA and non-MIA CEU, Western blot, immunoprecipitation and transfection experiments were performed. RESULTS. Non-MIA CEU do not activate p38, as opposed to MIA, and the extent of ERK and JNK activation is lower than in response to MIA. The effect of MIA and non-MIA CEU on focal adhesion associated protein was also studied; MIA were shown to induce focal adhesion dismantlement associated with a sustained increase in paxillin phosphorylation and FAK cleavage, as opposed to non-MIA CEU. In addition, bcl-2 phosphorylation and AKT cleavage, induced by all MIA tested, was not observed in response to non-MIA CEU further emphasizing the differential cell death mechanisms induced by MIA and non-MIA CEU. Pharmacologic and genetic approaches emphasize that the ASK1-p38 pathway activation contributes to the cytotoxic mechanism of MIA, in contrast to non-MIA CEU. ASK1-p38 is important for increased paxillin phosphorylation and FAK cleavage, suggesting that ASK-1-p38 is an upstream event of FA structure dismantlement induced by MIA. Moreover, the endogen inhibitor of ASK-1, thioredoxin, is released from ASK-1 in response to MIA as opposed to non-MIA CEU. CONCLUSION. Our study supports that ASK1-p38 activation is an important signaling event, induced by MIA, which impairs focal adhesion structure and induces anchorage-dependent apoptosis or anoikis.
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Rodrı́guez-Fernández, José Luis, Manuel Gómez, Alfonso Luque, Nancy Hogg, Francisco Sánchez-Madrid, and Carlos Cabañas. "The Interaction of Activated Integrin Lymphocyte Function-associated Antigen 1 with Ligand Intercellular Adhesion Molecule 1 Induces Activation and Redistribution of Focal Adhesion Kinase and Proline-rich Tyrosine Kinase 2 in T Lymphocytes." Molecular Biology of the Cell 10, no. 6 (June 1999): 1891–907. http://dx.doi.org/10.1091/mbc.10.6.1891.
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Integrin receptors play a central role in the biology of lymphocytes, mediating crucial functional aspects of these cells, including adhesion, activation, polarization, migration, and signaling. Here we report that induction of activation of the β2-integrin lymphocyte function-associated antigen 1 (LFA-1) in T lymphocytes with divalent cations, phorbol esters, or stimulatory antibodies is followed by a dramatic polarization, resulting in a characteristic elongated morphology of the cells and the arrest of migrating lymphoblasts. This cellular polarization was prevented by treatment of cells with the specific tyrosine kinase inhibitor genistein. Furthermore, the interaction of the activated integrin LFA-1 with its ligand intercellular adhesion molecule 1 induced the activation of the cytoplasmic tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK-2). FAK activation reached a maximum after 45 min of stimulation; in contrast, PYK-2 activation peaked at 30 min, declining after 60 min. Upon polarization of lymphoblasts, FAK and PYK-2 redistributed from a diffuse localization in the cytoplasm to a region close to the microtubule-organizing center in these cells. FAK and PYK-2 activation was blocked when lymphoblasts were pretreated with actin and tubulin cytoskeleton-interfering agents, indicating its cytoskeletal dependence. Our results demonstrate that interaction of the β2-integrin LFA-1 with its ligand intercellular adhesion molecule 1 induces remodeling of T lymphocyte morphology and activation and redistribution of the cytoplasmic tyrosine kinases FAK and PYK-2.
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Kuo, Hsing-Chun, Yur-Ren Kuo, Kam-Fai Lee, Meng-Chiao Hsieh, Cheng-Yi Huang, Yung-Yu Hsieh, Ko-Chao Lee, et al. "A Comparative Proteomic Analysis of Erinacine A’s Inhibition of Gastric Cancer Cell Viability and Invasiveness." Cellular Physiology and Biochemistry 43, no. 1 (2017): 195–208. http://dx.doi.org/10.1159/000480338.
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Background / Aims: Erinacine A, isolated from the ethanol extract of the Hericium erinaceus mycelium, has been demonstrated as a new alternative anticancer medicine. Drawing upon current research, this study presents an investigation of the molecular mechanism of erinacine A inhibition associated with gastric cancer cell growth. Methods: Cell viability was determined by Annexin V–FITC/propidium iodide staining and migration using a Boyden chamber assay to determine the effects of erinacine A treatment on the proliferation capacity and invasiveness of gastric cancer cells. A proteomic assay provided information that was used to identify the differentially-expressed proteins following erinacine A treatment, as well as the mechanism of its targets in the apoptotic induction of erinacine A. Results: Our results demonstrate that erinacine A treatment of TSGH 9201 cells increased cytotoxicity and the generation of reactive oxygen species (ROS), as well as decreased the invasiveness. Treatment of TSGH 9201 cells with erinacine A resulted in the activation of caspases and the expression of TRAIL. Erinacine A induction of apoptosis was accompanied by sustained phosphorylation of FAK/AKT/p70S6K and the PAK1 pathways, as well as the generation of ROS. Furthermore, the induction of apoptosis and anti-invasion properties by erinacine A could involve the differential expression of the 14-3-3 sigma protein (1433S) and microtubule-associated tumor suppressor candidate 2 (MTUS2), with the activation of the FAK/AKT/p70S6K and PAK1 signaling pathways. Conclusions: These results lead us to speculate that erinacine A may generate an apoptotic cascade in TSGH 9201 cells by activating the FAK/AKT/p70S6K/PAK1 pathway and upregulating proteins 1433S and MTUS2, providing a new mechanism underlying the anti-cancer effects of erinacine A in human gastric cancer cells.
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Xie, Zhigang, Kamon Sanada, Benjamin Adam Samuels, Heather Shih, and Li-Huei Tsai. "Serine 732 Phosphorylation of FAK by Cdk5 Is Important for Microtubule Organization, Nuclear Movement, and Neuronal Migration." Cell 114, no. 4 (August 2003): 469–82. http://dx.doi.org/10.1016/s0092-8674(03)00605-6.
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Pham, Dinh-Chuong, Yu-Chuan Chang, Shian-Ren Lin, Yuh-Ming Fuh, May-Jywan Tsai, and Ching-Feng Weng. "FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells." Molecules 23, no. 12 (November 28, 2018): 3110. http://dx.doi.org/10.3390/molecules23123110.
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Human neuroblastoma cancer is the most typical extracranial solid tumor. Yet, new remedial treatment therapies are demanded to overcome its sluggish survival rate. Neferine, isolated from the lotus embryos, inhibits the proliferation of various cancer cells. This study aimed to evaluate the anti-cancer activity of neferine in IMR32 human neuroblastoma cells and to expose the concealable molecular mechanisms. IMR32 cells were treated with different concentrations of neferine, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess cell viability. In an effort to determine the molecular mechanisms in neferine-incubated IMR32 cells, cell cycle arrest, cell migration, and focal adhesion kinase (FAK), the 70-kDa ribosomal S6 kinase 1 (S6K1), poly (ADP-ribose) polymerase (PARP), caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3 (LC3) protein expressions were investigated. Neferine strongly disrupted the neuroblastoma cell growth via induction of G2/M phase arrest. Furthermore, neferine provoked autophagy and apoptosis in IMR32 cells, confirmed by p-FAK, and p-S6K1 reduction, LC3-II accumulation, Beclin-1 overexpression, and cleaved caspase-3/PARP improvement. Finally, neferine markedly retarded cell migration of neuroblastoma cancer cells. As a result, our findings for the first time showed an explicit anti-cancer effect of neferine in IMR32 cells, suggesting that neferine might be a potential candidate against human neuroblastoma cells to improve clinical outcomes with further in vivo investigation.
Dissertations / Theses on the topic "FAK, microtubule"
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Rea, K. "FOCAL ADHESION KINASE INVOLVEMENT IN MODULATING THE PROLIFERATION OF TUMOR CELLS." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/273483.
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The focal adhesion kinase (FAK) is well characterized non-receptor tyrosine kinase, although it undergoes also to phosphorylation on serine residues whose role is not fully understood. FAK is ubiquitously expressed and plays a crucial role as integrator of signaling from either integrins or Receptor Tyrosine Kinases (RTKs) and has been linked to cell transformation and progression in many solid tumors. Among those, the Epithelial Ovarian Cancer (EOC) has a different behaviour during progression: it rarely metastasizes to distant sites but disseminate within the peritoneal cavity.
Our attention was focused on the characterization of the role of FAK in different type of tumor cells and in particular on the phosphorylation (P) on the serine 732 of FAK (P-FAKSer732). We found that P-FAKSer732 was present at variable levels in cancer cell lines but its activation was independent from integrin engagement and from the kinase activity of FAK. P-FAKSer732 was not localized at the focal adhesion site during migration but it was accumulated in dividing cells, co-localizing with the tubulin of the spindle during mitosis and regulating microtubule (MT) polymerization and mitotic spindle formation. CDK5 was identified as the specific kinase responsible for FAK serine phosphorylation whose activation was induced by EGF stimulation of the EGFR/ERK signalling. Thus, we have identified for the first time the axis EGFR/MEK/ERK/CDK5/P-FAKSer732 as a novel pathway leading to mitosis of tumor cells.
We next aimed to identify the mechanism governing the crosstalk between adhesion molecules and RTKs thus leading to proliferation, migration and invasion of tumor cells. I focused my analysis on EOC which is the main cancer histotype studied in our laboratory. We therefore investigated in EOC cells a possible role of E-cadherin (cadh) to contribute to the novel signalling pathway described above. Indeed, we found that E-cadh was the adhesion molecule necessary for the formation of the EOC multi-cellular aggregates (MCAs) present in the ascites. The E-cadh and CDK5 resulted to be necessary to the generation of FAKSer732 and this protein complex was necessary for the EGF-mediated EGFR activation likely due to the stabilization of EGFR protein on the cell membrane. In line with these results, E-cadh expressing EOC cells were more susceptible to the CDK5 inhibitor, roscovitine. These data demonstrated a pivotal role of E-cadh in contributing to the proliferation of EOC MCAs.
To clarify the processes responsible for the switch from a proliferative to a more invasive phenotype of EOC MCAs necessary for tumor dissemination, we were studied another RTK, Axl whose expression has been already reported to be associated to a more invasive phenotype. We found that the stimulation of Axl by its ligand Gas6 required the engagement of β3-integrin with components of the extra-cellular matrix (ECM). The crosstalk between Gas6/Axl and the integrin signallings was independent by FAK but required the contribution of p130Cas, a scaffold protein involved in the transmission of the ECM-integrin signalling, for adhesion, migration and invasion of EOC cells. Indeed, the lack of p130Cas decreased the level of Gas6-dependent Axl activation and inhibited Gas6-induced EOC cells adhesion, migration and invasion. In 56 out of 72 EOC biopsies, Axl and p130Cas were significantly co-expressed indicating of a collaborative signaling between Axl and p130Cas also in vivo. We have identified an Axl signalling which requires a p130Cas-mediated crosstalk with integrins for the dissemination of EOCs. Altogether, our investigation allowed the definition of two novel adhesion-dependent signalling pathways which drive the proliferation and the invasion of EOC cells, respectively. The inhibition of these pathways will likely affect EOC MCA growth as well as the invasion of EOC solid primary and secondary lesions.
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Estes, Brett. "THE FAR C-TERMINUS OF TPX2 CONTRIBUTES TO SPINDLE MORPHOGENESIS." 2017. https://scholarworks.umass.edu/masters_theses_2/462.
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A cell must build a bipolar mitotic spindle in order to faithfully segregate replicated DNA. To do so, multiple microtubule nucleation pathways are utilized to generate the robust spindle apparatus. TPX2, a microtubule binding protein, holds crucial roles in both the Ran-dependent and Augmin-dependent pathways where microtubules are nucleated near the chromosomes and from pre-existing microtubules. However, the exact role TPX2 plays in branching microtubules is less understood. Here, we explored the effect of truncating the essential TPX2 C-terminal 37 amino acids on Augmin localization and branching microtubule activity. First, we depleted LLC-Pk1 cells of the Augmin subunit HAUS6 and show that microtubule nucleation around the chromosomes following a nocodazole washout is strongly reduced leading to exaggerated kinetochore microtubule growth. Next, we depleted endogenous TPX2 in LLC-Pk1 cells harboring full length or truncated TPX2 bacterial artificial chromosome (BAC) DNA. Results show that TPX2 710 LAP cells have reduced Augmin localization on the spindle fibers, which correlates with reduced microtubule regrowth in the chromosomal region. In TPX2 710 LAP cells, regrowth was like Augmin depleted cells. Therefore, we provide evidence that the far C-terminus of TPX2 is required for branching microtubule nucleation and that kinetochore microtubule growth is Augmin-independent. In addition, we investigated cell cycle regulation of TPX2 by mutating the S738 phosphosite in the C-terminal motor interacting region. We utilized BAC recombineering to create phospho-mimetic and phospho-null mutants. In combination with plasmid DNA knockdown/rescue, overexpression and spindle assembly assays, we show that the phosphorylation of the C-terminal domain contributes to early mitotic events. LLC-Pk1 cells showed a significant increase in aberrant spindle morphology and reduced spindle stability in the presence of 738A and absence of endogenous TPX2. While rescue with the alanine mutant caused in an increase in multipolar spindles, overexpression resulted in a strong dominant negative monopolar phenotype. Therefore, S738 appears to contribute to mitotic force regulation during mitosis. In conclusion, the far C-terminus of TPX2 and its regulation play a role in the formation of a proper mitotic spindle.
Book chapters on the topic "FAK, microtubule"
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Moriarty, Philip. "Nanomachines." In Nanotechnology: A Very Short Introduction, 93—C5F4. Oxford University PressOxford, 2022. http://dx.doi.org/10.1093/actrade/9780198841104.003.0005.
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Abstract This chapter describes how nature has harnessed nanotechnology from the start of life on Earth to perform a variety of essential functions. It analyses the sophistication, intricacy, and elegance of nature’s nanomachinery, which far outstrips anything that scientists are capable of creating. It also discusses how the natural world is awash with molecular machines that achieve unidirectional motion with no need for an external guiding intelligence. The chapter mentions the STM-powered nanocar, a biomolecular motor from the kinesin family that leaves its synthetic counterpart in the dust in very many ways. It explains how kinesin converts chemical energy into mechanical movement, transporting its molecular cargo along tracks known as microtubules.
Conference papers on the topic "FAK, microtubule"
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Sharp, Kendra V., and Ronald J. Adrian. "Shear-Induced Arching of Particle-Laden Flows in Microtubes." In ASME 2001 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2001. http://dx.doi.org/10.1115/imece2001/mems-23879.
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Abstract Despite the growing interest in microfluidic systems, the study of two-phase flows in such systems thus far has been somewhat limited in scope. Examples of recent studies of two-phase flows in microchannels include flows containing liquid and gas (Tran, 1998; Stanley, 1997), the dispersion of laminar fluid streams (Galambos, 1998), and the flow of very dilute particle suspensions through micropumps (Jang et al., 1999). The present experiments identify ‘shear-induced arching’ as a new mechanism causing microtube blockage. This mechanism is most likely to occur when 0.33D < dp < 0.46D, where dp is the particle diameter and D is the microtube diameter, and was observed for flows of particle-laden fluids with concentration, ϕ, as low as 0.5%. Following a simple geometrical analysis, for 0.33D < dp < 0.46D, it can be shown that once the particles are in the arching configuration, lateral forces induced by the shear on the arch can hold the particles in place and stabilize the arch. Experiments were performed over a range of particle-to-rube diameter ratios. As predicted, if enough of the particles in any given experiment had a diameter of 0.33D–0.46D, blockages occurred in the microtube.
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Buehler, Markus J., and Zhao Qin. "Structure Prediction and Nanomechanical Properties of Human Vimentin Intermediate Filament Dimers." In ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-204824.
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Intermediate filaments (IFs), in addition to microtubules (MTs) and microfilaments (MFs), are one of the three major components of the cytoskeleton in eukaryotic cells. As the basic building block of IFs, the properties of the IF dimmer re crucial to fully understand the molecular basis for the properties of the IF network in cells. However, the structure of IF dimers remains unknown, which has thus far prevented the elucidation of its nanomechanical properties, in particular molecular-level mechanisms of deformation. Here we present the development of a full atomistic molecular model of the vimentin dimmer, a coiled-coil structure consisting of four alpha-helixes (AHs). The structure is found to be stable in molecular dynamics simulation after an extensive equilibration process. After careful structure prediction, the behavior of the IF dimer under mechanical stress is investigated; including studies of changing the pulling velocity and a detailed analysis of the associated deformation and rupture mechanisms. Most notably, we observe a transition of AHs to beta-sheets (BSs) under mechanical deformation, as has been observed indirectly in earlier experimental studies. Our result helps to better understand the structure and fracture mechanism of this important protein filament.
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Nathan, Ashwin S., Brendon M. Baker, and Robert L. Mauck. "Cytoskeletal Control of Mesenchymal Stem Cell Nuclear Deformation on Nanofibrous Scaffolds." In ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-206855.
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Nanofibrous scaffolds hold great potential for tissue engineering as they recapitulate the mechanical and topographic features of fibrous tissues on both the macroscopic and microscopic level [1,2]. When seeded with cells capable of fibrous extracellular matrix (ECM) production such as mesenchymal stem cells (MSCs), the new matrix is deposited in accordance with the underlying topography, and scaffolds develop improved mechanical properties with time in free swelling culture [6]. While promising, the free swelling conditions employed in evaluating in vitro construct maturation have thus far remained insufficient in achieving native-level properties. As most fibrous tissues are subjected to loading in vivo, mechanical conditioning is considered critical in directing tissue development and subsequent homeostasis with normal use. Mechanical signals are translated from the ECM to the nucleus via the cytoskeleton, with signals culminating in the control of biosynthetic activity based upon external loading conditions. Various bioreactor systems have been developed to mimic these in vivo conditions towards enhancing the maturation of engineered constructs, with most focusing on dynamic tensile deformation [3,4]. Towards gaining further insight into the means by which mechanical cues inspire alterations in cellular behavior, this study developed methods for evaluating cell and sub-cellular deformation of MSCs seeded on randomly-oriented and aligned nanofibrous scaffolds. Using a device that enables visualization of cells seeded on nanofibrous scaffolds undergoing static tensile deformation, we examined the effect of applied strain rate on cell adhesion to scaffolds, as well as changes in nuclear shape in the context of viable actin and microtubule sub-cellular networks with applied strain. These data provide new insight into fundamental mechanisms of MSC mechanoregulation on nanofibrous scaffolds, and offer constraints for long-term bioreactor studies.
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Muszbek, L., R. Adåny, M. A. Glukhova, M. G. Frid, A. E. Kabakov, and V. E. Kot-e-liansky. "THE IDENTIFICATION OF VIMENTIN, AN INTERMEDIATE,FILAMENT SUBUNIT PROTEIN IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643900.
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In platelets the presence of basic subunit proteins of microtubules as well as microfilaments has been verified a long time ago and it was also shown that both of these cytoskeletal systems go through a tremendous reorganization during the activation process. Surprisingly, none of the components of intermediate filaments has so far been identified in these cells, perhaps because platelets were considered too motile to have intermediate filaments, the most static structures among the three major cytoskeletal systems. By using two different monoclonal antibodies (II C4 and II D8) here we attempted to establish if vimen-tin, an intermediate filament subunit protein present in most differentiating cells, in cells grown in tissue culture and in certain fully differentiated cells also exists in human platelets The IgM type antibodies were characterized by various immuno-morphological and immunobiochemical techniques. They labelled selectively colcemid-sensitive filamentous structures in fibroblasts, in endothelial cells and in vascular but not myometrium smooth muscle and were shown to be monospecific against epitopes on vimentin in fibroblast homogenate. When whole platelet homogenate was submitted to high resolution gradient SDS PAGE and then electroblotted to nitrocellulose sheet, both antibodies reacted with a single protein band of 55 kD that comigrated with fibroblast vimentin. By immunofluorescence microscopy an annular ring-like structure was stained for vimentin that suggests a membran skeletal role for this protein. During pseu-dopode formation a redistribution of vimentin could be observed. Parallel with the disappearance of ring-like structures vimentin appears in pseudopodia suggesting that like in the case of other filamentous systems platelet activation induces a structural reorganization of the intermediate filaments, as well.
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Mendygarin, Yertay, Luis R. Rojas-Solórzano, Nurassyl Kussaiyn, Rakhim Supiyev, and Mansur Zhussupbekov. "Eulerian-Eulerian Multiphase Modeling of Blood Cells Segregation in Flow Through Microtubes." In ASME 2017 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2017. http://dx.doi.org/10.1115/imece2017-70850.
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Cardiovascular Diseases, the common name for various Heart Diseases, are responsible for nearly 17.3 million deaths annually and remain the leading global cause of death in the world. It is estimated that this number will grow to more than 23.6 million by 2030, with almost 80% of all cases taking place in low and middle income countries. Surgical treatment of these diseases involves the use of blood-wetted devices, whose relatively recent development has given rise to numerous possibilities for design improvements. However, blood can be damaged when flowing through these devices due to the lack of biocompatibility of surrounding walls, thermal and osmotic effects and most prominently, due to the excessive exposure of blood cells to shear stress for prolonged periods of time. This extended exposure may lead to a rupture of membrane of red blood cells, resulting in a release of hemoglobin into the blood plasma, in a process called hemolysis. Moreover, exposure of platelets to high shear stresses can increase the likelihood of thrombosis. Therefore, regions of high shear stress and residence time of blood cells must be considered thoroughly during the design of blood-contacting devices. Though laboratory tests are vital for design improvements, in-vitro experiments have proven to be costly, time-intensive and ethically controversial. On the other hand, simulating blood behavior using Computational Fluid Dynamics (CFD) is considered to be an inexpensive and promising tool to help predicting blood damage in complex flows. Nevertheless, current state-of-the-art CFD models of blood flow to predict hemolysis are still far from being fully reliable and accurate for design purposes. Previous work have demonstrated that prediction of hemolysis can be dramatically improved when using a multiphase (i.e., phases are plasma, red blood cells and platelets) model of the blood instead of assuming the blood as a homogeneous mixture. Nonetheless, the accurate determination of how the cells segregate becomes the critical issue in reaching a truthful prediction of blood damage. Therefore, the attempt of this study is to develop and validate a numerical model based on Granular Kinetic Theory (GKT) for solid phases (i.e., cells treated as particles) that provides an improved prediction of blood cells segregation within the flow in a microtube. Simulations were based on finite volume method using Eulerian-Eulerian modeling for treatment of three-phase (liquid-red blood cells and platelets) flow including the GKT to deal with viscous properties of the solid phases. GKT proved to be a good model to predict particle concentration and pressure drop by taking into account the contribution of collisional, kinetic and frictional effects in the stress tensor of the segregated solid phases. Preliminary results show that the improved segregated model leads to a better prediction of spatial distribution of blood cells. Simulations were performed using ANSYS FLUENT platform.
Reports on the topic "FAK, microtubule"
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Hoffman, Wesley P., Hong T. Phan, and Phillip G. Wapner. The Far-Reaching Nature of Microtube Technology. Fort Belvoir, VA: Defense Technical Information Center, January 1998. http://dx.doi.org/10.21236/ada397880.
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