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Integrin talin

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https://www.readbyqxmd.com/read/28183734/skap2-is-required-for-%C3%AE-2-integrin-mediated-neutrophil-recruitment-and-functions
#1
Mark Boras, Stephanie Volmering, Arne Bokemeyer, Jan Rossaint, Helena Block, Bernadette Bardel, Veerle Van Marck, Barbara Heitplatz, Stefanie Kliche, Annegret Reinhold, Clifford Lowell, Alexander Zarbock
Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment...
February 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28157452/activated-%C3%AE-2-integrins-restrict-neutrophil-recruitment-during-murine-acute-pseudomonal-pneumonia
#2
Zachary S Wilson, Lawrence B Ahn, William S Serratelli, Matthew D Belley, Joanne Lomas-Neira, Mehmet Sen, Craig T Lefort
Rapid neutrophil recruitment is critical for the efficient clearance of bacterial pathogens from the lungs. While β2 integrins and their activation are required for neutrophil recruitment from postcapillary venules of the systemic circulation into inflamed tissues, the involvement of integrins in neutrophil recruitment in response to respiratory infection varies between bacterial pathogens. For stimuli eliciting β2 integrin-dependent neutrophil influx, including Pseudomonas aeruginosa, it remains unclear whether the activation of β2 integrins is an essential step in this process...
February 3, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28155884/the-molecular-basis-of-talin2-s-high-affinity-toward-%C3%AE-1-integrin
#3
Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P Hytönen, Chang-Guo Zhan, Cai Huang
Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β-integrin tails...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28135265/%C3%AE-integrin-de-phosphorylation-by-the-density-enhanced-phosphatase-dep-1-attenuates-egfr-signaling-in-c-elegans
#4
Michael Walser, Christoph Alois Umbricht, Erika Fröhli, Paolo Nanni, Alex Hajnal
Density-Enhanced Phosphatase-1 (DEP-1) de-phosphorylates various growth factor receptors and adhesion proteins to regulate cell proliferation, adhesion and migration. Moreover, dep-1/scc1 mutations have been detected in various types of human cancers, indicating a broad tumor suppressor activity. During C. elegans development, DEP-1 mediates binary cell fate decisions by negatively regulating EGFR signaling. Using a substrate-trapping DEP-1 mutant in a proteomics approach, we have identified the C. elegans β-integrin subunit PAT-3 as a specific DEP-1 substrate...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28117756/talin-modulation-by-a-synthetic-n-acylurea-derivative-reduces-angiogenesis-in-human-endothelial-cells
#5
I-Rang Lim, Hyung Joon Joo, Minseon Jeong, Jong-Ho Kim, Seung-Cheol Choi, Chungho Kim, Jong-Wha Jung, Soon Jun Hong
Talin is a focal adhesion protein that activates integrins and recruits other focal adhesion proteins. Talin regulates the interactions between integrins and the extracellular matrix, which are critical for endothelial cells during angiogenesis. In this study, we successfully synthesized a novel talin modulator, N-((2-(1H-indol-3-yl)ethyl)carbamoyl)-2-(benzo[d][1,3]dioxol-5-yloxy)acetamide, referred to as KCH-1521. KCH-1521 was determined to bind talin and modulate downstream signaling molecules of talin. After 24 h of treatment, KCH-1521 changed the cell morphology of human umbilical vein endothelial cells (HUVECs) and reduced focal adhesion protein expression including vinculin and paxillin...
January 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28101696/role-of-the-helix-in-talin-f3-domain-f3-helix-in-talin-mediated-integrin-activation
#6
Ang Li, Qiang Guo, Ailin Wei, Yaliang Zhou, Weiming Hu
Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin αIIbβ3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin's capacity to activate integrin has never been explored before...
January 18, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28096216/basal-filopodia-and-vascular-mechanical-stress-organize-fibronectin-into-pillars-bridging-the-mesoderm-endoderm-gap
#7
Yuki Sato, Kei Nagatoshi, Ayumi Hamano, Yuko Imamura, David Huss, Seiichi Uchida, Rusty Lansford
Cells may exchange information with other cells and tissues by exerting forces on the extracellular matrix (ECM). Fibronectin (FN) is an important ECM component that forms fibrils through cell contacts and creates directionally biased geometry. Here, we demonstrate that FN is deposited as pillars between widely separated germ layers, namely the somitic mesoderm and the endoderm, in quail embryos. Alongside the FN pillars, long filopodia protrude from the basal surfaces of somite epithelial cells. Loss-of-function of Ena/VASP, α5β1-integrins or talin in the somitic cells abolished the FN pillars, indicating that FN pillar formation is dependent on the basal filopodia through these molecules...
January 15, 2017: Development
https://www.readbyqxmd.com/read/28052935/d120-and-k152-within-the-ph-domain-of-t-cell-adapter-skap55-regulate-plasma-membrane-targeting-of-skap55-and-lfa-1-affinity-modulation-in-human-t-lymphocytes
#8
Amelie Witte, Bernhard Meineke, Jana Sticht, Lars Philipsen, Benno Kuropka, Andreas J Müller, Christian Freund, Burkhart Schraven, Stefanie Kliche
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its Pleckstrin Homology (PH) domain...
January 4, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27974389/structure-and-lipid-binding-properties-of-the-kindlin-3-pleckstrin-homology-domain
#9
Tao Ni, Antreas C Kalli, Fiona B Naughton, Luke A Yates, Omar Naneh, Mirijam Kozorog, Gregor Anderluh, Mark S P Sansom, Robert J C Gilbert
Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain (4.1-erythrin-radixin-moiesin domain) comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at a resolution of 2.23 Å and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics simulations suggest flexibility in the PH domain loops connecting β-strands forming the putative phosphatidylinositol phosphate (PtdInsP)-binding site...
February 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/27910855/l-type-calcium-channels-regulate-filopodia-stability-and-cancer-cell-invasion-downstream-of-integrin-signalling
#10
Guillaume Jacquemet, Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu, Johanna Ivaska
Mounting in vitro, in vivo and clinical evidence suggest an important role for filopodia in driving cancer cell invasion. Using a high-throughput microscopic-based drug screen, we identify FDA-approved calcium channel blockers (CCBs) as potent inhibitors of filopodia formation in cancer cells. Unexpectedly, we discover that L-type calcium channels are functional and frequently expressed in cancer cells suggesting a previously unappreciated role for these channels during tumorigenesis. We further demonstrate that, at filopodia, L-type calcium channels are activated by integrin inside-out signalling, integrin activation and Src...
December 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/27803165/g%C3%AE-13-switch-region-2-relieves-talin-autoinhibition-to-activate-%C3%AE-iib%C3%AE-3-integrin
#11
James Schiemer, Andrew Bohm, Li Lin, Glenn Merrill-Skoloff, Robert Flaumenhaft, Jin-Sheng Huang, Guy C Le Breton, Athar H Chishti
Integrins function as bi-directional signaling transducers that regulate cell-cell and cell-matrix signals across the membrane. A key modulator of integrin activation is talin, a large cytoskeletal protein that exists in an autoinhibited state in quiescent cells. Talin is a large 235-kDa protein composed of an N-terminal 45-kDa FERM (4.1, ezrin-, radixin-, and moesin-related protein) domain, also known as the talin head domain, and a series of helical bundles known as the rod domain. The talin head domain consists of four distinct lobes designated as F0-F3...
December 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27775029/protein-kinase-d1-regulates-focal-adhesion-dynamics-and-cell-adhesion-through-phosphatidylinositol-4-phosphate-5-kinase-type-l-%C3%AE
#12
Nisha Durand, Ligia I Bastea, Jason Long, Heike Döppler, Kun Ling, Peter Storz
Focal adhesions (FAs) are highly dynamic structures that are assembled and disassembled on a continuous basis. The balance between the two processes mediates various aspects of cell behavior, ranging from cell adhesion and spreading to directed cell migration. The turnover of FAs is regulated at multiple levels and involves a variety of signaling molecules and adaptor proteins. In the present study, we show that in response to integrin engagement, a subcellular pool of Protein Kinase D1 (PKD1) localizes to the FAs...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27769864/hmgb1-induces-human-non-small-cell-lung-cancer-cell-motility-by-activating-integrin-%C3%AE-v%C3%AE-3-fak-through-tlr4-nf-%C3%AE%C2%BAb-signaling-pathway
#13
Jianhua Zhu, Jing Luo, Yongchao Li, Min Jia, Yueqin Wang, Yan Huang, Shuhong Ke
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein with multi-functions and plays an important role in tumorigenesis and metastasis in various human cancers. In the present study, we found that HMGB1 induced migration of in human non-small cell lung cancer (NSCLC) cells by up-regulating integrin αvβ3 expression. Further investigation evidenced that HMGB1 activated Toll-like receptor 4 (TLR4) and NF-κB, which was responsible for αvβ3 up-regulation. Furthermore, HMGB1-induced integrin αvβ3 expression led to focal adhesion kinase (FAK) phosphorylation and increased paxillin and talin mRNA expression...
October 18, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27760339/the-integrin-lfa-1-controls-t-follicular-helper-cell-generation-and-maintenance
#14
Alexandre P Meli, Ghislaine Fontés, Danielle T Avery, Scott A Leddon, Mifong Tam, Michael Elliot, Andre Ballesteros-Tato, Jim Miller, Mary M Stevenson, Deborah J Fowell, Stuart G Tangye, Irah L King
T follicular helper (Tfh) cells are a CD4(+) T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection...
October 18, 2016: Immunity
https://www.readbyqxmd.com/read/27749372/the-role-of-kindlin-in-neutrophil-recruitment-to-inflammatory-sites
#15
Anika Stadtmann, Alexander Zarbock
PURPOSE OF REVIEW: Since the discovery of the lack of kindlin-3 expression as the reason for the immunopathology leukocyte adhesion deficiency III syndrome, the role of kindlin-3 in inflammatory processes was investigated in a numerous studies. This review gives an overview about recent findings regarding the role of kindlin-3 in neutrophil activation and recruitment. RECENT FINDINGS: Kindlin-3, together with talin-1, contributes essentially to the activation of β2-integrins in neutrophils...
January 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/27737925/the-integrin-talin-complex-under-force
#16
Jan Neumann, Kay-Eberhard Gottschalk
Integrins are the major transmembrane cellular adhesion receptors. Talin binds to integrins with its head domain and links them to the actin cytoskeleton with its rod domain, acting as the force linkage between the extracellular matrix and the cytoskeleton. It is unknown how forces in different directions affect the integrin-talin complex. We show that small forces applied to the integrin-talin complex breaks a salt bridge between the integrins α- and β-subunit, unlocking the integrin from its resting state...
October 13, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27737911/drosophila-vinculin-is-more-harmful-when-hyperactive-than-absent-and-can-circumvent-integrin-to-form-adhesion-complexes
#17
Aidan P Maartens, Jutta Wellmann, Emma Wictome, Benjamin Klapholz, Hannah Green, Nicholas H Brown
Vinculin is a highly conserved protein involved in cell adhesion and mechanotransduction, and both gain and loss of its activity causes defective cell behaviour. Here, we examine how altering vinculin activity perturbs integrin function within the context of Drosophila development. Whereas loss of vinculin produced relatively minor phenotypes, gain of vinculin activity, through a loss of head-tail autoinhibition, caused lethality. The minimal domain capable of inducing lethality is the talin-binding D1 domain, and this appears to require talin-binding activity, as lethality was suppressed by competition with single vinculin-binding sites from talin...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27722656/the-key-position-influence-of-staple-location-on-constrained-peptide-conformation-and-binding
#18
Kelly L Keeling, Okki Cho, Denis B Scanlon, Grant W Booker, Andrew D Abell, Kate L Wegener
Constrained α-helical peptides are showing potential as biological probes and therapeutic agents that target protein-protein interactions. However, the factors that determine the optimal constraint locations are still largely unknown. Using the β-integrin/talin protein interaction as a model system, we examine the effect of constraint location on helical conformation, as well as binding affinity, using circular dichroism and NMR spectroscopy. Stapling increased the overall helical content of each integrin-based peptide tested...
October 18, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27721490/coordinated-integrin-activation-by-actin-dependent-force-during-t-cell-migration
#19
Pontus Nordenfelt, Hunter L Elliott, Timothy A Springer
For a cell to move forward it must convert chemical energy into mechanical propulsion. Force produced by actin polymerization can generate traction across the plasma membrane by transmission through integrins to their ligands. However, the role this force plays in integrin activation is unknown. Here we show that integrin activity and cytoskeletal dynamics are reciprocally linked, where actin-dependent force itself appears to regulate integrin activity. We generated fluorescent tension-sensing constructs of integrin αLβ2 (LFA-1) to visualize intramolecular tension during cell migration...
October 10, 2016: Nature Communications
https://www.readbyqxmd.com/read/27694340/talin2-mediated-traction-force-drives-matrix-degradation-and-cell-invasion
#20
Lei Qi, Naser Jafari, Xiang Li, Zaozao Chen, Liqing Li, Vesa P Hytönen, Benjamin T Goult, Chang-Guo Zhan, Cai Huang
Talin binds to β-integrin tails to activate integrins, regulating cell migration, invasion and metastasis. There are two talin genes, TLN1 and TLN2, encoding talin1 and talin2, respectively. Talin1 regulates focal adhesion dynamics, cell migration and invasion, whereas the biological function of talin2 is not clear and, indeed, talin2 has been presumed to function redundantly with talin1. Here, we show that talin2 has a much stronger binding to β-integrin tails than talin1. Replacement of talin2 Ser339 with Cys significantly decreased its binding to β1-integrin tails to a level comparable to that of talin1...
October 1, 2016: Journal of Cell Science
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