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Journal articles on the topic "Talin inhibitor"
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BASS, Mark D., Bipin PATEL, Igor G. BARSUKOV, Ian J. FILLINGHAM, Robert MASON, Beverley J. SMITH, Clive R. BAGSHAW, and David R. CRITCHLEY. "Further characterization of the interaction between the cytoskeletal proteins talin and vinculin." Biochemical Journal 362, no. 3 (March 8, 2002): 761–68. http://dx.doi.org/10.1042/bj3620761.
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The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1—VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498–636; VBS2, residues 727–965; and VBS3, residues 1943–2157) each bind tightly to the same or overlapping sites within vinculin1–258. A short synthetic talin VBS3 peptide (residues 1944–1969) was sufficient to inhibit binding of a 125I-labelled talin VBS3 polypeptide to vinculin1–258, and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin1–258. Binding of the 125I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin1–258 using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1–131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh—Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh—Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.
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Dai, Baiyun, Peng Wu, Feng Xue, Renchi Yang, Ziqiang Yu, Kesheng Dai, Changgeng Ruan, Gang Liu, Peter J. Newman, and Cunji Gao. "Integrin-αIIbβ3-mediated outside-in signalling activates a negative feedback pathway to suppress platelet activation." Thrombosis and Haemostasis 116, no. 11 (September 2016): 918–30. http://dx.doi.org/10.1160/th16-02-0096.
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SummaryIntegrin-αIIbβ3-mediated outside-in signalling is widely accepted as an amplifier of platelet activation; accumulating evidence suggests that outside-in signalling can, under certain conditions, also function as an inhibitor of platelet activation. The role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation is disputable. We employed flow cytometry, aggregometry, immunoprecipitation, and immunoblotting to investigate the role of integrin-αIIbβ3-mediated outside-in signalling in platelet activation. Integrin αIIbβ3 inhibition enhances agonist-induced platelet ATP secretion. Human platelets lacking expression of αIIbβ3 exhibited more platelet ATP secretion than their wild-type counterparts. Moreover, integrin-αIIbβ3-mediated outside-in signals activate SHIP-1, which in turn mediates p-Akt dep-hosphorylation, leading to inactivation of PI3K/Akt signalling. Furthermore, 3AC (SHIP-1 inhibitor) inhibits platelet disaggregation, and promotes platelet ATP secretion. Upon ADP stimulation, Talin is recruited to αIIbβ3, and it is dissociated from αIIbβ3 when platelets disaggregate. In addition, treatment with RUC2, an inhibitor of αIIbβ3, which blocks αIIbβ3-mediated outside-in signalling, can markedly prevent the dissociation of talin from integrin. SHIP1 Inhibitor 3AC inhibits the dissociation of talin from integrin-β3. These results suggest that integrin-αIIbβ3-mediated outside-in signalling can serve as a brake to restrict unnecessary platelet activation by activated SHIP-1, which mediated the disassociation of talin from β3, leading to integrin inactivation and blocking of PI3K/Akt signalling to restrict platelet ATP secretion.
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Koh, Timothy J., and James G. Tidball. "Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells." American Journal of Physiology-Cell Physiology 279, no. 3 (September 1, 2000): C806—C812. http://dx.doi.org/10.1152/ajpcell.2000.279.3.c806.
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We tested the hypothesis that nitric oxide can inhibit cytoskeletal breakdown in skeletal muscle cells by inhibiting calpain cleavage of talin. The nitric oxide donor sodium nitroprusside prevented many of the effects of calcium ionophore on C2C12muscle cells, including preventing talin proteolysis and release into the cytosol and reducing loss of vinculin, cell detachment, and loss of cellular protein. These results indicate that nitric oxide inhibition of calpain protected the cells from ionophore-induced proteolysis. Calpain inhibitor I and a cell-permeable calpastatin peptide also protected the cells from proteolysis, confirming that ionophore-induced proteolysis was primarily calpain mediated. The activity of m-calpain in a casein zymogram was inhibited by sodium nitroprusside, and this inhibition was reversed by dithiothreitol. Previous incubation with the active site-targeted calpain inhibitor I prevented most of the sodium nitroprusside-induced inhibition of m-calpain activity. These data suggest that nitric oxide inhibited m-calpain activity via S-nitrosylation of the active site cysteine. The results of this study indicate that nitric oxide produced endogenously by skeletal muscle and other cell types has the potential to inhibit m-calpain activity and cytoskeletal proteolysis.
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Zhang, Jingying Sarah, William E. Kraus, and George A. Truskey. "Stretch-induced nitric oxide modulates mechanical properties of skeletal muscle cells." American Journal of Physiology-Cell Physiology 287, no. 2 (August 2004): C292—C299. http://dx.doi.org/10.1152/ajpcell.00018.2004.
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In this study, we examined the hypothesis that stretch-induced (nitric oxide) NO modulates the mechanical properties of skeletal muscles by increasing accumulation of protein levels of talin and vinculin and by inhibiting calpain-induced proteolysis, thereby stabilizing the focal contacts and the cytoskeleton. Differentiating C2C12 myotubes were subjected to a single 10% step stretch for 0–4 days. The apparent elastic modulus of the cells, Eapp, was subsequently determined by atomic force microscopy. Static stretch led to significant increases ( P < 0.01) in Eapp beginning at 2 days. These increases were correlated with increases in NO activity and neuronal NO synthase (nNOS) protein expression. Expression of talin was upregulated throughout, whereas expression of vinculin was significantly increased only on days 3 and 4. Addition of the NO donor l-arginine onto stretched cells further enhanced Eapp, NOS activity, and nNOS expression, whereas the presence of the NO inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) reversed the effects of mechanical stimulation and of l-arginine. Overall, viscous dissipation, as determined by the value of hysteresis, was not significantly altered. For assessment of the role of vinculin and talin stability, cells treated with l-NAME showed a significant decrease in Eapp, whereas addition of a calpain inhibitor abolished the effect. Thus our results show that NO inhibition of calpain-initiated cleavage of cytoskeleton proteins was correlated with the changes in Eapp. Together, our data suggest that NO modulates the mechanical behavior of skeletal muscle cells through the combined action of increased talin and vinculin levels and a decrease in calpain-mediated talin proteolysis.
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Shen, Bo, Xiaojuan Zhao, Kelly A. O'Brien, Aleksandra Stojanovic-Terpo, Michael Keegan Delaney, Kyungho Kim, Jaehyung Cho, Stephen C. T. Lam, and Xiaoping Du. "A Mechanism For Switch Of Integrin Signaling Direction and a New Anti-Thrombotic Strategy Through Selective Outside-In Signaling Inhibition." Blood 122, no. 21 (November 15, 2013): 2295. http://dx.doi.org/10.1182/blood.v122.21.2295.2295.
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Abstract Antagonists of platelet integrin alphaIIbbeta3 are potent anti-thrombotics due to critical roles of integrins in thrombosis. However, integrins are also important in hemostasis, and thus integrin antagonists have potentially life-threatening bleeding side effect. It would be ideal if we can develop integrin antagonists without bleeding side effect. Integrins transmit signals bidirectionally. Intracellular signals activate integrin alphaIIbbeta3, leading to talin-dependent integrin ligation, which is required for platelet adhesion and initial hemostatic thrombus formation. Integrin ligation in turn mediates Galpha13/Src-dependent outside-in signaling that stabilizes and amplify thrombi, which is crucial for occlusive arterial thrombosis. Here we show that talin and Galpha13 bind to mutually exclusive but distinct sites in integrin beta3, and their bindings are dynamically regulated during integrin signaling. The first talin binding wave mediates inside-out signaling and also “ligand-induced integrin activation”, but is not required for early phase outside-in signaling. Integrin ligation induces talin dissociation and Galpha13 binding, which selectively mediates early phase outside-in signaling. The second talin binding wave is associated with late phase outside-in signaling and clot retraction. Based on these findings, we have designed a selective inhibitor of Galpha13-integrin interaction, which specifically abolished outside-in signaling without affecting inside-out signaling and integrin ligation. Strikingly, this inhibitor potently inhibits occlusive thrombosis in vivo, but has no effect on tail bleeding time, in contrast to the current integrin antagonists. Thus, we have discovered a mechanism for switching the direction of integrin signaling and a new anti-thrombotic that does not cause bleeding. Disclosures: No elevant conflicts of interest to declare.
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Yuan, Weiping, Tina M. Leisner, Andrew W. McFadden, Zhengyan Wang, Mark K. Larson, Shantres Clark, Christel Boudignon-Proudhon, Stephen C. T. Lam, and Leslie V. Parise. "CIB1 is an endogenous inhibitor of agonist-induced integrin αIIbβ3 activation." Journal of Cell Biology 172, no. 2 (January 16, 2006): 169–75. http://dx.doi.org/10.1083/jcb.200505131.
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In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of αIIbβ3 is believed to occur in part via engagement of the β3 cytoplasmic tail with talin; however, the role of the αIIb tail and its potential binding partners in regulating αIIbβ3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the αIIb tail, is an endogenous inhibitor of αIIbβ3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced αIIbβ3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to αIIbβ3, thus providing a model for tightly controlled regulation of αIIbβ3 activation.
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Mason, Christopher, Stephen Lynch, James Benjamin, Dani Ashak, Jamunabai M. Prakash, Andrew Moore, Pamela Bagsiyao, et al. "Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin." Thrombosis and Haemostasis 111, no. 01 (2014): 140–53. http://dx.doi.org/10.1160/th13-03-0248.
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SummaryMatrix metalloproteinase (MMP) activity is generally associated with normal or pathological extracellular processes such as tissue remodeling in growth and development or in tumor metastasis and angiogenesis. Platelets contain at least three MMPs, 1, 2 and 9 that have been reported to stimulate or inhibit agonist-induced platelet aggregation via extracellular signals. The non-selective Zn+2 chelating MMP inhibitor, 1,10-phenanthroline, and the serine protease inhibitor, AEBSF, were found to inhibit all tested agonist-induced platelet aggregation reactions. In vitro analysis demonstrated that 1,10-phenanthroline completely inhibited MMP-1,2,and 9 but had little to no effect on calpain activity while the converse was true with AEBSF. We now demonstrate that MMP-2 functions intracellularly to regulate agonistinduced platelet aggregations via the hydrolytic activation of talin, the presumed final activating factor of glycoprotein (GP)IIb/IIIa integrin (the inside-out signal). Once activated GPIIb/IIIa binds the dimeric fibrinogen molecule required for platelet aggregation. The active intracellular MMP-2 molecule is complexed with JAK 2/STAT 3, as demonstrated by the fact that all three proteins are co-immunoprecipitated with either anti-JAK 2, or anti-STAT 3 antibodies and by immunofluorescence studies. The MMP-2 platelet activation pathway can be synergistically inhibited with the non-selective MMP inhibitor, 1,10-phenanthroline, plus a JAK 2 inhibitor. This activation pathway is distinct from the previously reported calpain-talin activating pathway. The identification of a new central pathway for platelet aggregation presents new potential targets for drug regulation and furthers our understanding of the complexity of platelet activation mechanisms.
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Lewis, J. M., D. A. Cheresh, and M. A. Schwartz. "Protein kinase C regulates alpha v beta 5-dependent cytoskeletal associations and focal adhesion kinase phosphorylation." Journal of Cell Biology 134, no. 5 (September 1, 1996): 1323–32. http://dx.doi.org/10.1083/jcb.134.5.1323.
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Integrins alpha v beta 3 and alpha v beta 5 both mediate cell adhesion to vitronectin yet trigger different postligand binding events. Integrin alpha v beta 3 is able to induce cell spreading, migration, angiogenesis, and tumor metastasis without additional stimulators, whereas alpha v beta 5 requires exogenous activation of protein kinase C (PKC) to mediate these processes. To investigate this difference, the ability of beta 3 or beta 5 to induce colocalization of intracellular proteins was assessed by immunofluorescence in hamster CS-1 melanoma cells. We found that alpha v beta 5 induced colocalization of talin, alpha-actinin, tensin, and actin very weakly relative to alpha v beta 3. alpha v beta 5 was able to efficiently induce colocalization of focal adhesion kinase (FAK); however, it was unable to increase phosphorylation of FAK on tyrosine. Activation of PKC by adding phorbol ester to alpha v beta 5-expressing cells induced spreading, increased colocalization of alpha-actinin, tensin, vinculin, p130cas and actin, and triggered tyrosine phosphorylation of FAK. Unexpectedly, talin colocalization remained low even after activation of PKC. Treatment of cells with the PKC inhibitor calphostin C inhibited spreading and the colocalization of talin, alpha-actinin, tensin, and actin for both alpha v beta 3 and alpha v beta 5. We conclude that PKC regulates localization of cytoskeletal proteins and phosphorylation of FAK induced by alpha v beta 5. Our results also show that FAK can be localized independent of its phosphorylation and that cells can spread and induce localization of other focal adhesion proteins in the absence of detectable talin.
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Feng, Shuju, Xin Lu, and Michael H. Kroll. "A Contractile Cytoskeletal Tether Modulates Signaling between Glycoprotein Ibα and αIIbβ3." Blood 104, no. 11 (November 16, 2004): 1554. http://dx.doi.org/10.1182/blood.v104.11.1554.1554.
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Abstract In resting platelets, the cytoplasmic domains of glycoprotein (Gp) Ibα and β3 integrin link the GpIb-IX-V and αIIbβ3 complex with adapter proteins, cytoskeletal elements and lipid and tyrosine kinases. Biochemical and pharmacological analyses of intact platelets and genetic analyses of recombinant GpIb-IX-V and αIIbβ3 in CHO cells point towards the hypothesis that a series of cytoskeletal proteins form a functional tether connecting the cytoplasmic domains of GpIbα and β3 integrin. To test the hypothesis that dynamic contractility of this tether modulates VWF-induced signaling between GpIb-IX-V and αIIbβ3, we examined how pathological shear stress affects connections between tethering elements and how altering the contractile function of the tether affects VWF-induced platelet adherence and aggregation. We observed in resting platelets that there is no co-immunoprecipitation of GpIbα and αIIbβ3. The large dimeric actin-binding protein filamin A co-immunoprecipitates with both GpIbα and β3 integrin, but its association with αIIbβ3 is inhibited by DNaseI, indicating that it binds indirectly to αIIbβ3 through cytoskeletal connections. These connections were investigated in resting platelets by examining a series of immunoprecipitates (IP) for co-precipitating proteins using immunoblotting (IB). We observed the following IP/IB pairs [(+) designates that the co-precipitation is DNaseI-sensitive]: β3/talin (+); talin/α-actinin (+); talin/vinculin (+); and talin/filamin A (−). We also observed that myosin heavy chain (MHC) and the tyrosine kinase Syk co-immunoprecipitate with αIIbβ3 in resting platelets. When washed platelets in buffer containing calcium (1 mM) and VWF (5 μg/ml) were sheared at 120 dynes/cm2 for 2 minutes, the cytoskeletal linkage separates: there was enhanced filamin A, actin and α-actinin binding to GpIbα, enhanced vinculin binding to α-actinin, enhanced talin binding to αIIbβ3, and both myosin and the tyrosine kinase Syk disassociated from the β3 tail. Inhibiting myosin contractility with the myosin light chain kinase (MLCK) inhibitor ML-9 (1 mM) inhibited the shear-induced association between talin and β3, as well as platelet aggregation in response to 120 dynes/cm2 in the cone plate viscometer and platelet-dependent thrombosis from whole blood onto type I collagen in a parallel plate flow chamber with a shear rate of 500 sec−1 (shear stress of ~ 20 dynes/cm2). The data presented support a model of shear-induced platelet aggregation in which a series of cytoskeletal proteins serve as a mechanotransducing scaffolding linking the cytoplasmic domains of GpIbα and β3 integrin. When GpIb-IX-V engages ligand under shearing forces, the force is transduced from GpIbα to filamin to actin/α-actinin to vinculin to talin to β3, and contractility driven by the activation of αIIbβ3-associated myosin enhances talin binding to β3, thereby effecting a conformation change that creates a ligand-receptive αIIbβ3. Such interactions may be regulated by cytosolic ionized calcium (which effects MLCK activation) and tyrosine kinases (αIIbβ3-associated Syk disassociates from β3 following shear). These results provide evidence that the structural scaffolding connecting GpIb-IX-V with αIIbβ3 localizes signaling elements to functionally important compartments that modulate αIIbβ3 activation and shear-induced platelet aggregation.
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Litvinov, Rustem I., Karen Pei Yi Fong, Oleg V. Kim, Kathleen I. Molnar, Paul C. Billings, Alex Sternisha, James A. Wells, John W. Weisel, William F. DeGrado, and Joel S. Bennett. "Active Calpain Promotes Fibrin Clot Contraction By Strengthening the Coupling of Fibrin-Bound αIIbβ3 to the Platelet Cytoskeleton." Blood 132, Supplement 1 (November 29, 2018): 1128. http://dx.doi.org/10.1182/blood-2018-99-113063.
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Abstract Platelet-driven blood clot contraction reduces and compacts clot volume, promoting hemostasis while restoring blood flow past otherwise obstructive thrombi. Clot contraction is driven by traction forces in the range of tens of pN per platelet that are generated by platelet non-muscle myosin IIa and actin on αIIbβ3 bound to extracellular fibrin fibers. In an analysis of the kinetics of thrombin-induced clot formation and contraction in platelet-rich plasma, we found that clot contraction has two discernable phases: an exponential initiation phase and a second exponential contraction phase. It is noteworthy that Azam et al (Mol Cell Biol21:2213-20, 2001) observed that deleting the µ-calpain gene in mice impairs platelet-mediated clot contraction. In this context, we found that inhibiting calpain activity with ALLM (N-Acetyl-Leu-Leu-Methional), a cell-permeable calpain inhibitor, significantly prolonged the duration of the initiation phase and decreased the kinetic rate constants for both the initiation and contraction phases of thrombin-stimulated platelet-mediated clot contraction, but without affecting the overall extent of contraction. The calpain inhibitor ALLN (N-acetyl-Leu-Leu-Norleu) had the same effect. Thus, these studies imply that activation of platelet calpain facilitates the transmission of traction forces from the platelet cytoskeleton to the αIIbβ3 bound to fibrin fibers. μ-Calpain is calcium-dependent cytosolic neutral cysteine protease that is activated 30-60 seconds after the onset of platelet aggregation stimulated by platelet agonists such as thrombin. To identify the calpain-cleaved protein or proteins involved in clot contraction, we incubated washed human platelets with the thrombin activation peptide TRAP in the presence or absence of calpain inhibitors and identified calpain-cleaved proteins using subtiligase-mediated biotin-labeling of nascent N-termini followed by mass spectrometry. We identified 32 proteins in the platelet cytosol that undergo calpain-mediated cleavage after TRAP stimulation. Many of these are cytoskeletal proteins, most prominently talin which connects integrins to the cytoskeleton and vinculin which is required for myosin-contractility-dependent effects on traction force and adhesion strength. Accordingly, we focused our attention on these two proteins. Talin, a 250 kD protein, is composed of a 45 kD N-terminal head domain attached via a flexible linker to a 200 kD C-terminal rod domain. The rod domain consists of 62 amphipathic α-helices organized into a series of four- and five-helix bundles. Vinculin is a 116 kD protein composed of 5 domains and has an autoinhibited structure in which domains 1-3 bind to domain 5. We detected 8 calpain-mediated cleavages in talin, 2 previously identified cleavage sites in unstructured regions and 6 others in α-helical regions known to interact with other proteins. Four of the latter are located within the first 12 talin helices, a region that contains four vinculin binding sites (VBSs). Likewise, the remaining two cleavage sites are in proximity to a VBS. A VBS is a vinculin-binding α-helix that is buried in a helical bundle due to extensive hydrophobic interactions with other amphipathic helices. Because VBS are packed into the interior of a helical bundle, a structural rearrangement is required to initiate vinculin binding. Using magnetic tweezers and atomic force microscopy, del Rio et al demonstrated that force-induced stretching of single talin rod molecules activates VBSs (Science323:638-41, 2009)), implying that stretching causes the conformational change required to expose buried VBSs. Thus, based on the location of the calpain-mediated cleavages in talin, we hypothesize that by cleaving talin in proximity to a VBS, calpain facilitates vinculin to binding talin, thereby strengthening the coupling of fibrin-bound αIIbβ3 to the platelet cytoskeleton to promote fibrin clot contraction. Disclosures No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "Talin inhibitor"
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Vigouroux, Clémence. "Regulation of actin assembly and mechanotransduction in cell-matrix adhesion complexes by the protein RIAM The PIP2-talin-RIAM-VASP pathway controls actin polymerization and organisation Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force Integrin-bound talin head inhibits actin filament barbed-end elongation." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL015.
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Lors de la migration cellulaire, les complexes d’adhérence contrôlent la production de force et l’adaptation aux propriétés mécaniques de l’environnement. Le but de ce projet était de comprendre les mécanismes moléculaires par lesquels ces complexes contrôlent la force produite par l’assemblage du cytosquelette d’actine et codent une information mécanique en réaction biochimique. La première étude montre que les protéines taline, RIAM et VASP s’assemblent à la surface d’une membrane pour stimuler l’assemblage de l’actine par un nouveau mécanisme. La deuxième partie est basée sur la reconstitution de la machinerie mécano-sensible des complexes d’adhérence avec des protéines pures sur une surface micro-imprimée observée en microscopie. L’étude montre que la protéine étirable taline échange son partenaire RIAM contre la vinculine en réponse à la force du cytosquelette. La taline code donc l’information mécanique en recrutant les partenaires qui correspondent à son degré d’étirementDuring cell migration, adhesion complexes control the production of force and the adaptation to the mechanical properties of the environment. The aim of this project was to understand the molecular mechanisms by which these complexes control the force produced by actin assembly and encode mechanical information into biochemical reactions. The first study shows that the proteins talin, RIAM and VASP assemble on the surface of a membrane to stimulate actin assembly by a novel. mechanism The second part is based on the reconstitution of the mechanosensitive machinery of the adhesion complexes with pure proteins on a micropatterned surface observed in microscopy. The study reveals that the stretchable protein talin exchanges its partner RIAM for vinculin in response to the force transmitted by the actin cytoskeleton. Talin thus codes mechanical information by recruiting partners that correspond to its degree of stretch
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Rafiei, Shahrzad. "Talin : a novel inducible antagonist of transforming growth factor-beta 1 (TGF-[beta]1) signal transduction." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100203.
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The survival of breast cancer patients declines when tumors are invasive and have an increased possibility of metastasizing to distal sites. Transforming Growth Factor-beta (TGF-beta) suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells. However, at late stage of mammary carcinogenesis, due to genetic and epigenetic alterations, TGF-beta loses its cytostatic actions, and contributes to tumor invasion by promoting cell proliferation, Actin cytoskeletal reorganization, as well as Epithelial to Mesenchymal Transition (EMT). Despite the key role of TGF-beta1 in tumor suppression as well as tumor progression, the molecular mechanisms underlying the conversion of TGF-beta form an inhibitor of proliferation in mammary breast cancer cells to an inducer of their cell growth and EMT have not been fully elucidated. Thus, acquiring a basic knowledge on the mechanism of TGF-beta regulating its target genes and its contribution to cancer progression may highlight new avenues for cancer therapy development. This prompted us to further investigate and identify TGF-beta-inducible genes that may be involved in TGF-beta biological responses during tumorigenesis.In this thesis, we identified Talin as a novel TGF-beta1 target gene that acts as an antagonist to inhibit TGF-beta-mediated cell growth arrest and transcriptional activity in mammary cancer cell line, MCF-7. Searching for new partners of activated Smads, we found that TGF-beta1 induces Talin translocation from cytosol to the plasma membrane where Talin physically interacts with the TGF-beta1 signaling components, the Smads and the receptors. Furthermore, we observed that TGF-beta1 stimulation leads to the formation of Actin stress fibers where Talin was detected at the end of these stress fibers. Taken all together, the obtained data show that TGF-beta1 positively induced expression of Talin and suggests a role for Talin, which acts as a negative feedback loop to control TGF-beta biological responses.
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Wang, Hong. "Regulation of actin polymerization by cell-matrix adhesion complexes : a biochemical study of the talin-vinculin complex Integrin-bound talin head inhibits actin filament barbed-end elongation Talin and vinculin combine their individual activities to trigger actin assembly The C-terminal domain of EFA6A interacts directly with F-actin and assembles F-actin bundles." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS132.
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Pour migrer efficacement dans différents tissus, les cellules doivent détecter et s'adapter aux variations des propriétés mécaniques de leur environnement. Dans ce processus d’adaptation, les adhérences focales (AF) renforcent leur lien avec la matrice extracellulaire et le cytosquelette d'actine. En réponse à la force, l'association de la taline et de la vinculine pourrait renforcer l'ancrage de l'actine aux AF en contrôlant l'assemblage de l'actine par un mécanisme inconnu. Des études antérieures ont montré que la vinculine contient un seul domaine de liaison à l'actine (ABD) qui lie les filaments d’actine, coiffe les extrémités barbées des filaments d’actine et nuclée des filaments d'actine. La taline contient également trois ABD mais leur capacité à réguler l'assemblage de l'actine n'était pas connue avant ce projet. L'objectif global de ce projet de thèse était de déterminer les mécanismes précis par lesquels le complexe taline-vinculine contrôle l'assemblage de l'actine en réponse à la force. Dans une première partie de ce projet de thèse, préalable à l'étude du complexe taline-vinculine, j'ai terminé la caractérisation de la taline. J'ai démontré que le domaine ABD1 de la taline bloque l'allongement des extrémités barbées des filaments d'actine observés en microscopie à fluorescence (TIRFM), alors que ABD2 et ABD3 n'affectent pas la dynamique de l'actine. Dans la deuxième partie de ce projet, j'ai déterminé l'activité du complexe taline-vinculine. Parce que la force est nécessaire pour déclencher l'association de la vinculine à la taline, et parce que les deux protéines sont auto-inhibées, il a jusqu'à présent été difficile de déterminer la capacité du complexe taline-vinculine à réguler la polymérisation de l'actine. Par conséquent, nous avons d'abord conçu des mutants de taline et de vinculine qui s'associent de manière constitutive en un complexe stable. En combinant des études cinétiques en spectroscopie de fluorescence, des tests de liaison à l’actine et l’observation de filaments d’acine uniques en microscopie TIRF, nous avons déterminé les activités de ces mutants et de leurs complexes sur la dynamique de l'actine. Notre étude a d'abord révélé que les trois activités de la vinculine sont contrôlées par des contacts auto-inhibiteurs spécifiques. Nous montrons également que des suppressions d'hélice le long de la taline exposent les sites voisins de liaison à la vinculine, imitant ainsi l'étirement mécanique de la taline. L'association des mutants de taline aux mutants de vinculine forme un complexe qui nuclée des filaments coiffés à leur extrémité barbée. La caractérisation d'une série de complexes, dans lesquels la vinculine et la taline sont amputés de divers ABD, révèle la contribution de chaque protéine dans ce mécanisme. En conclusion, nos données suggèrent un mécanisme pour le renforcement de l'ancrage de l'actine dans les AF en réponse à la forceTo migrate efficiently in different tissues, cells must sense and adapt to variations of the mechanical properties of their environment. In this adaptive process, focal adhesions (FAs) strengthen their link with the extracellular matrix and the actin cytoskeleton. The force-dependent association of the actin binding proteins talin and vinculin could reinforce actin anchoring to FAs by controlling actin assembly though an unknown mechanism. Previous studies showed that vinculin contains a single actin-binding domain (ABD) which binds to actin filaments, caps actin filament barbed-ends and nucleates actin filaments. Talin also contains three ABDs but their ability to regulate actin assembly was not known before this project. The global objective of this PhD project was to determine the precise mechanisms by which the force-dependent talin-vinculin complex controls actin assembly. In a first part of this PhD project, as a prerequisite to the study of the talin-vinculin complex, I finished the characterization of talin. I demonstrated that the N-terminal ABD1 of talin blocks the elongation of actin filament barbed ends observed in fluorescent microscopy (TIRFM), whereas ABD2 and ABD3 do not affect actin dynamics. In the second and main part of this project, I determined the activity of the talin-vinculin complex. Because force is required to trigger vinculin association to talin, and because both proteins are autoinhibited, it has so far been difficult to determine the ability of the talin-vinculin complex to regulate actin polymerization. Therefore, we first designed talin and vinculin mutants that associate constitutively into a stable complex. By combining fluorescence spectroscopy, binding assays and single filament observation in TIRF microscopy, we determined the activities of these mutants and their complex on actin dynamics. Our study first revealed that the three activities of vinculin are controlled by specific auto-inhibitory contacts. We also show that helix deletions along the rod domain of talin expose neighboring vinculin-binding sites, mimicking the mechanical stretching of talin. The binding of these talin and vinculin mutants forms a complex that nucleates filaments capped at their barbed ends. The characterization of a series of complexes, in which vinculin and talin are deleted from various ABDs, reveals the contribution of each protein in this mechanism. Altogether our data suggest a mechanism for the force-dependent reinforcement of actin anchoring in FAs
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Keeling, Kelly Lee. "A study on side chain linked peptides, toward the development of talin inhibitors using β3 integrin peptide analogues." Thesis, 2018. http://hdl.handle.net/2440/128465.
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This thesis discusses the design and production of peptides with side chain linkers that are intended to bind to the F3 domain of talin. The talin F3 domain was targeted as it is involved in the activation of integrin membrane proteins present in platelets. The over activation of these integrins can result in clotting within the blood vessels causing heart disease, however, current medication targeting integrin have negative side effects. The design and synthesis of short peptides based on the sequence of the β3 integrin tail that binds to the F3 domain of talin is presented. The binding affinity of peptides to the talin F3 domain was tested using NMR titrations to reveal the ideal location for the linker in the production of potential therapeutics which target integrin activation. Side chain linked peptides with high helical content have previously been shown to improve binding affinity. This drove investigation of side chain constrained peptides to increase their helical content, and thus, their binding affinity to talin F3 domain and cellular uptake. It is demonstrated that side chain linkers are effective in stabilising the helical structure of the short peptides. When incorporated in the β3 integrin sequence in specific locations, lactam linkers improved binding affinity of these peptides to the talin F3 domain. Additionally, all-hydrocarbon and triazole linkers enhanced the peptide’s cellular uptake when compared to the native peptide of this sequence. The position and type of side chain linkers were investigated. The result of which showed that the position of the linker had a significant impact on the binding affinity to talin. The lactam linker between residues in positions 725 and 729 created a peptide (7) with the highest binding affinity. The cell penetration of peptides with different linker types was tested using NIH 3T3 mouse cells, and HEK298 cells. A number of side chain linkers were tested with the triazole linker producing the most α-helical peptide, and the all-hydrocarbon linker producing peptides with the greatest cellular uptake.Thesis (Ph.D.) -- University of Adelaide, School of Physical Sciences, 2018
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Dreyer, Timothy James. "Talen-mediated homology directed insertion of anti-viral sequences to inhibit hepatitis B viral gene expression and replication." Thesis, 2015. http://hdl.handle.net/10539/18492.
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More than 350 million people are chronic hepatitis B virus (HBV) carriers. Viral covalently closed circular DNA (cccDNA) persists as a replication intermediate and can remain dormant. Current HBV therapeutics do not eradicate viral cccDNA reservoirs. Transcription activator-like effector nucleases (TALENs) target and cleave specific DNA sequences, and have shown promise as antiviral agents. Here we propose TALEN-mediated homology directed disruption and silencing of the cccDNA. The designer TALENs introduce double stranded breaks (DSBs) at the HBV cccDNA core and surface ORFs, which activate the non-homologous end joining (NHEJ) and homology directed repair (HDR) cellular repair pathways. We utilise the HDR process to introduce specific mutations at the TALEN cleavage sites. Here we facilitate integration of a HBV-targeting artificial primary micro RNA (pri-miR) mimic into the HBV genome by co-introducing TALENs and donor template strands that contain a pri-miR cassette flanked by sequences that are homologous to the TALEN target sites. Integration of the donor sequences was evaluated by PCR and disruption of HBV replication was evaluated using ELISA. HBsAg knockdown when targeting the surface and core targets was 94% and 63% respectively, a significant improvement on use of TALENs alone. PCR analysis and sequencing confirmed successful integration of donor sequences into the HBV core and surface target sites, verifying that HBsAg knockdown is as a result of sequence insertion and possible pri-miR-mediated silencing of HBx. In conclusion, integration of an artificial DNA sequence at specific HBV target sites was demonstrated and the synergistic activity of TALENs and donor template strands shows promising anti-HBV abilities. Results of this study provide the means to improve targeted disruption of HBV DNA by TALEN constructs. Moreover, the potential for combining different anti-HBV gene therapies to result in better viral suppression is demonstrated
Book chapters on the topic "Talin inhibitor"
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Tiplic, Dijana, and Eyvind Elstad. "Forhold ved skolen som påvirker skolelederens tilfredshet med jobben." In Hva kan vi lære av TALIS 2018?, 21–33. Cappelen Damm Akademisk/NOASP, 2021. http://dx.doi.org/10.23865/noasp.123.ch2.
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School aspects that influence the principals’ job-satisfaction This article aims to analyze how different school relations can influence principals’ job satisfaction. Our analysis is based on TALIS survey data from 162 Norwegian principals. We have used Structural Equation Modelling (SEM) to analyze statistical relations between several potential explaining variables and principals’ professional and individual job satisfaction. The main findings show that innovation support and stress are statistically related to principals’ job satisfaction with school. On the other hand, principals’ teaching support is not related to their job satisfaction with school. In addition, principals’ perception of stress is negatively related to several positively charged characteristics of school as an organization (innovation support, teaching support, and job satisfaction with school). Possible interpretations of the findings are that innovation support contributes to job satisfaction with school but that stress can be perceived as an inhibitory factor in principals’ work. This article focuses on stress that involves a work overload from following up on teachers’ professional development, having too much administrative work, as well as having extra work due to staff absence. This stress is primarily related to a connection between principals’ working capacity and their ambitions to execute their leadership goals. Implications for practice and further research are discussed.
Conference papers on the topic "Talin inhibitor"
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Ryan, Dorothy M., Emer P. Reeves, Noel G. McElvaney, and Shane O'Neill. "Secretory Leukoprotease Inhibitor Prevents Talin Cleavage Via Calpain Inhibition Thereby Influencing Neutrophil Cytoskeletal Rearrangement." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a2430.
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Golji, Javad, and Mohammad R. K. Mofrad. "Focal Adhesion Mechanotransduction: Molecular Events Leading to Vinculin Activation." In ASME 2010 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2010. http://dx.doi.org/10.1115/sbc2010-19711.
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Focal adhesions are formed as a molecular glue linking cytoskeletal actin filaments to the extracellular matrix (ECM). They are formed at the site of mechanical stimulation (1) and involve and initial recruitment of talin and vinculin to ECM bound integrin molecules at the site of external stimulation. Talin recruitment and its force-induced activation and subsequent interaction with vinculin have been extensively studied (2–4). Vinculin is natively in an auto-inhibited conformation and its activation involves removal of a steric hindrance preventing binding of Vt with actin (5) (Figure 1). Several hypotheses have been put forth regarding vinculin activation and its subsequent interaction with actin: 1) vinculin activation requires only interaction with talin at domain 1 (D1) (6), 2) a simultaneous interaction with both actin and talin is necessary to achieve vinculin activation (7), 3) once activated vinculin interacts with actin via an electrostatic interaction between Vt and two regions on F-actin (5). Each of these hypotheses is evaluated through molecular dynamics simulation and analysis.