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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
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
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...
October 5, 2016: Current Opinion in Hematology
Fa-Min Zeng, Yang-Min Xie, Lian-Di Liao, Li-Yan Li, Bo Chen, Jian-Jun Xie, Li-Yan Xu, En-Min Li
The key molecular events that contribute to tumorigenesis are incompletely understood. The aim of the present study was to characterize and compare the biological phenotypes of three human telomerase reverse transcriptase (hTERT) and/or human papillomavirus 16 E6 and E7‑immortalized esophageal epithelial cell lines, NE2‑hTERT (NE2), NE3‑E6E7‑hTERT (NE3) and NEcA6‑E6E7‑hTERT (NEcA6). The present study used soft‑agar colony formation assays, tumorigenicity assays in nude mice, and cell proliferation, adhesion and migration assays to identify the biological characteristics of NE2, NE3 and NEcA6 cells...
October 6, 2016: Molecular Medicine Reports
Dragica Spasojević, Danica Zmejkoski, Jasmina Glamočlija, Miloš Nikolić, Marina Soković, Verica Milošević, Ivana Jarić, Marijana Stojanović, Emilija Marinković, Talin Barisani-Asenbauer, Radivoje Prodanović, Miloš Jovanović, Ksenija Radotić
Nowadays bacterial resistance to known antibiotics is a serious health problem. In order to achieve more efficient treatment, lately there is an effort to find new substances, such as certain biomaterials, that are non-toxic to humans with antibiotic potential. Lignins and lignin-derived compounds have been proposed to be good candidates for use in medicine and health maintenance. In this study, the antibacterial activity of the lignin model polymer dehydrogenate polymer (DHP) in alginate hydrogel (Alg) was studied...
September 30, 2016: International Journal of Antimicrobial Agents
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
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, via 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...
October 13, 2016: Journal of Cell Science
Lisa S Thomas, Stephan R Targan, Masato Tsuda, Qi T Yu, Brenda C Salumbides, Talin Haritunians, Emebet Mengesha, Dermot P B McGovern, Kathrin S Michelsen
TL1A contributes to the pathogenesis of several chronic inflammatory diseases, including those of the bowel by enhancing TH1, TH17, and TH2 responses. TL1A mediates a strong costimulation of these TH subsets, particularly of mucosal CCR9(+) T cells. However, the signaling pathways that TL1A induces in different TH subsets are incompletely understood. We investigated the function of TL1A on human TH17 cells. TL1A, together with TGF-β, IL-6, and IL-23, enhanced the secretion of IL-17 and IFN-γ from human CD4(+) memory T cells...
October 12, 2016: Journal of Leukocyte Biology
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
Marjolein B M Meddens, Elvis Pandzic, Johan A Slotman, Dominique Guillet, Ben Joosten, Svenja Mennens, Laurent M Paardekooper, Adriaan B Houtsmuller, Koen van den Dries, Paul W Wiseman, Alessandra Cambi
Podosomes are cytoskeletal structures crucial for cell protrusion and matrix remodelling in osteoclasts, activated endothelial cells, macrophages and dendritic cells. In these cells, hundreds of podosomes are spatially organized in diversely shaped clusters. Although we and others established individual podosomes as micron-sized mechanosensing protrusive units, the exact scope and spatiotemporal organization of podosome clustering remain elusive. By integrating a newly developed extension of Spatiotemporal Image Correlation Spectroscopy with novel image analysis, we demonstrate that F-actin, vinculin and talin exhibit directional and correlated flow patterns throughout podosome clusters...
October 10, 2016: Nature Communications
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
Maria Kaisar, Leon F A van Dullemen, Marie-Laëtitia Thézénas, M Zeeshan Akhtar, Honglei Huang, Sandrine Rendel, Philip D Charles, Roman Fischer, Rutger J Ploeg, Benedikt M Kessler
BACKGROUND: The successful application of-omics technologies in the discovery of novel biomarkers and targets of therapeutic interventions is facilitated by large collections of well curated clinical samples stored in bio banks. Mining the plasma proteome holds promise to improve our understanding of disease mechanisms and may represent a source of biomarkers. However, a major confounding factor for defining disease-specific proteomic signatures in plasma is the variation in handling and processing of clinical samples leading to protein degradation...
2016: Clinical Proteomics
Youjun Li, Xiaoyong Luo, Yang Sun, Zhenyi Cui, Yizhou Liu, Rushi Liu, Xiangrong Guo
Focal adhesions are large multi-protein complexes that serve as the linkage between extracellular matrix (ECM) and actin cytoskeleton and control the network of signaling cascades underlying cell migration. Talin plays a key role in focal adhesion turnover, and calpain-mediated proteolysis of talin is central to focal adhesion disassembly, but its regulation is not well elucidated. Here we demonstrate that talin phosphorylation at three high stoichiometry sites on its head domain, T144 and T150, or S446, have contrasting effects on calpain-mediated cleavage of talin and cell migration by using site-directed mutagenesis to inhibit phosphorylation...
2016: Journal of Cancer
Karim Malki, Maria Grazia Tosto, Héctor Mouriño-Talín, Sabela Rodríguez-Lorenzo, Oliver Pain, Irfan Jumhaboy, Tina Liu, Panos Parpas, Stuart Newman, Artem Malykh, Lucia Carboni, Rudolf Uher, Peter McGuffin, Leonard C Schalkwyk, Kevin Bryson, Mark Herbster
Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline)...
October 1, 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
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
Steven R Brant, David T Okou, Claire L Simpson, David J Cutler, Talin Haritunians, Jonathan P Bradfield, Pankaj Chopra, Jarod Prince, Ferdouse Begum, Archana Kumar, Chengrui Huang, Suresh Venkateswaran, Lisa W Datta, Zhi Wei, Kelly Thomas, Lisa J Herrinton, Jan-Micheal A Klapproth, Antonio J Quiros, Jenifer Seminerio, Zhenqiu Liu, Jonathan S Alexander, Robert N Baldassano, Sharon Dudley-Brown, Raymond K Cross, Themistocles Dassopoulos, Lee A Denson, Tanvi A Dhere, Gerald W Dryden, John S Hanson, Jason K Hou, Sunny Z Hussain, Jeffrey S Hyams, Kim L Isaacs, Howard Kader, Michael D Kappelman, Jeffry Katz, Richard Kellermayer, Barbara S Kirschner, John F Kuemmerle, John H Kwon, Mark Lazarev, Ellen Li, David Mack, Peter Mannon, Dedrick E Moulton, Rodney D Newberry, Bankole O Osuntokun, Ashish S Patel, Shehzad A Saeed, Stephan R Targan, John F Valentine, Ming-Hsi Wang, Martin Zonca, John D Rioux, Richard H Duerr, Mark S Silverberg, Judy H Cho, Hakon Hakonarson, Michael E Zwick, Dermot P B McGovern, Subra Kugathasan
BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified [IBD-U]) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database)...
September 28, 2016: Gastroenterology
Shelby Calkins, Noha H Youssef
Focal adhesions (FAs) are large eukaryotic multiprotein complexes that are present in all metazoan cells and function as stable sites of tight adhesion between the extracellular matrix (ECM) and the cell's cytoskeleton. FAs consist of anchor membrane protein (integrins), scaffolding proteins (e.g. α-actinin, talin, paxillin, and vinculin), signaling proteins of the IPP complex (e.g. integrin-linked kinase, α-parvin, and PINCH), and signaling kinases (e.g. focal adhesion kinase (FAK) and Src kinase). While genes encoding complete focal adhesion machineries are present in genomes of all multicellular Metazoa; incomplete machineries were identified in the genomes of multiple non-metazoan unicellular Holozoa, basal fungal lineages, and amoebozoan representatives...
2016: PloS One
Joanna M Peloquin, Gautam Goel, Lingjia Kong, Hailiang Huang, Talin Haritunians, R Balfour Sartor, Mark J Daly, Rodney D Newberry, Dermot P McGovern, Vijay Yajnik, Sergio A Lira, Ramnik J Xavier
GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn's disease or ulcerative colitis and from healthy controls...
2016: JCI Insight
Hisashi Kato, Yozo Nakazawa, Yumi Kurokawa, Hirokazu Kashiwagi, Yoichiro Morikawa, Daisuke Morita, Fumiaki Banno, Shigenori Honda, Yuzuru Kanakura, Yoshiaki Tomiyama
Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1 activating molecule and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency...
September 23, 2016: Blood
Laura Lindsay, Samson N Dowland, Christopher R Murphy
Controlled ovarian hyperstimulation is an essential component of IVF techniques to ensure proliferation and development of multiple ovarian follicules but the effects of these hormones on the endometrium are largely unknown. During normal pregnancy in rats, there are significant changes in the basal plasma membrane of uterine epithelial cells (UECs) at the time of receptivity, including loss of focal adhesions. This enables the UECs to be removed from the implantation chamber surrounding the blastocyst, thus allowing invasion into the underlying stroma...
September 20, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
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