Abstract：
:Endothelial barrier dysfunction leads to edema and vascular leak, causing high morbidity and mortality. Previously, Abl kinase inhibition has been shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. We found that the inhibitor bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented lipopolysaccharide (LPS)-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, mitogen-activated protein 4 kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signaled via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Abl-related gene (Arg, also known as ABL2) by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. We conclude that MAP4K4 is an important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Because it inhibits both Arg and MAP4K4, use of the clinically available drug bosutinib might form a viable strategy against vascular leakage syndromes.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Botros L,Pronk MCA,Juschten J,Liddle J,Morsing SKH,van Buul JD,Bates RH,Tuinman PR,van Bezu JSM,Huveneers S,Bogaard HJ,van Hinsbergh VWM,Hordijk PL,Aman Jdoi
10.1242/jcs.240077subject
Has Abstractpub_date
2020-05-14 00:00:00issue
9eissn
0021-9533issn
1477-9137pii
jcs.240077journal_volume
133pub_type
杂志文章abstract：:Cofilin has emerged as a key regulator of actin dynamics at the leading edge of motile cells. Through its actin-severing activity, it creates new actin barbed ends for polymerization and also depolymerizes old actin filaments. Its function is tightly regulated in the cell. Spatially, its activity is restricted by othe...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.01631
更新日期：2005-01-01 00:00:00
abstract：:Telomere maintenance is essential for the unlimited proliferative potential of human cells, and hence immortalization. However, a number of tumors, tumor-derived cell lines and in vitro immortalized cell lines have been described that do not express detectable telomerase activity. These lines utilize a mechanism, term...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2000-12-01 00:00:00
abstract：:In a previous study we demonstrated that a homeobox peptide corresponding to the 60 amino acid long DNA-binding region of the Drosophila antennapedia homeo-protein was capable of crossing the plasma membrane of cells in culture. This finding has led us to investigate whether chimeric molecules encompassing the homeobo...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1992-08-01 00:00:00
abstract：:When migrating mesenchymal cells collide, they exhibit a 'contact inhibition of locomotion' response that results in reversal of their front-rear polarity by extension of a new leading edge, which enables their migration away from the opposing contacted cell. The critical cytoskeletal rearrangements underpinning these...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.087965
更新日期：2011-08-01 00:00:00
abstract：:Isoamyl alcohol (IAA) induces a phenotype that resembles pseudohyphae in the budding yeast Saccharomyces cerevisiae. We show here that IAA causes the rapid formation of linear chains of anucleate buds, each of which is accompanied by the formation of a septin ring at its neck. This process requires the activity of Swe...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00634
更新日期：2003-08-15 00:00:00
abstract：:Chloroquine resistance in the human malaria parasite, Plasmodium falciparum, arises from decreased accumulation of the drug in the ;digestive vacuole' of the parasite, an acidic compartment in which chloroquine exerts its primary toxic effect. It has been proposed that changes in the pH of the digestive vacuole might ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.02795
更新日期：2006-03-15 00:00:00
abstract：:The canonical Wnt/β-catenin signaling pathway regulates cell proliferation in development and adult tissue homeostasis. Dysregulated signaling contributes to human diseases, in particular cancer. Growing evidence suggests a role for clathrin and/or endocytosis in the regulation of this pathway, but conflicting results...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.244467
更新日期：2020-07-09 00:00:00
abstract：:In contrast to the highly dynamic actin cytoskeleton in non-muscle cells, actin filaments in muscle sarcomeres are thought to be relatively stable and undergo dynamics only at their ends. However, many proteins that promote rapid actin dynamics are also expressed in striated muscles. We show that a subset of actin fil...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.046805
更新日期：2009-06-15 00:00:00
abstract：:The nuclear division of Oxyrrhis marina is a very distinct one among the mitoses of dinoflagellates that have been studies. Using synchronized populations, we have investigated the ultrastructural changes in this nuclear division. In interphase, nuclei can be classified into two groups on the basis of the shapes of th...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1986-09-01 00:00:00
abstract：:Fluorescence in situ hybridization in combination with synaptonemal complex and spindle pole body immunostaining to both spread and structurally preserved nuclei from time course experiments disclosed prominent telomere clustering during meiotic prophase of the yeast Saccharomyces cerevisiae. It was found that centrom...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
abstract：:A comparison of stained cytosolic proteins, in vivo 80 S ribosome translation products and in vitro translation products of poly(A)+ RNA from three species of Acetabularia was performed after characterization of their molecular weights and isoelectric points via two-dimensional electrophoresis. A total of 803 stained ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1983-03-01 00:00:00
abstract：:SNARE [soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor] proteins control the membrane-fusion events of eukaryotic membrane-trafficking pathways. Specific vesicular and target SNAREs operate in specific trafficking routes, but the degree of specificity of SNARE functions is still elus...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.007948
更新日期：2007-09-15 00:00:00
abstract：:The plasma membrane Ca2+-ATPase-2 (PMCA2) is expressed in stereocilia of hair cells of the inner ear, whereas PMCA1 is expressed in the basolateral plasma membrane of hair cells. Both extrude excess Ca2+ from the cytosol. They are predicted to contain ten membrane-spanning segments, two large cytoplasmic loops as well...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.03030
更新日期：2006-07-15 00:00:00
abstract：:The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily -...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.203950
更新日期：2018-04-09 00:00:00
abstract：:Previously we have shown that the Saccharomyces cerevisiae CCZ1 (YBR131w) gene encodes a protein involved in protein trafficking. Deletion of this gene leads to fragmentation of the vacuole typical of the class B vps mutants. Genetic and biochemical data indicated that Ccz1p is required for fusion of various transport...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2001-09-01 00:00:00
abstract：:Sister chromatid cohesion is essential for proper segregation of the genome in mitosis and meiosis. Central to this process is cohesin, a multi-protein complex conserved from yeast to human. Previous genetic studies in fungi have identified Pds5/BimD/Spo76 as an additional factor implicated in cohesion. Here we descri...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.02355
更新日期：2005-05-15 00:00:00
abstract：:We investigated the effect of glucose deprivation treatment on clonogenicity in multidrug-resistant human breast carcinoma MCF-7/ADR cells. Survival of MCF-7/ADR cells decreased exponentially up to 8 hours of incubation in the glucose-free medium. The surviving fraction of these cells for 8 hours of glucose-deprivatio...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1997-03-01 00:00:00
abstract：:Previous work has shown that phorbol esters or diacylglycerol trigger cortical granule exocytosis in Xenopus oocytes. We sought to identify the isoform(s) of protein kinase C (PKC) that mediate(s) this regulated secretory event. Because this process is initiated by lipid activators of PKC but is independent of calcium...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2002-03-15 00:00:00
abstract：:The Tec kinases represent the second largest family of mammalian non-receptor tyrosine kinases and are distinguished by the presence of distinct proline-rich regions and pleckstrin homology domains that are required for proper regulation and activation. Best studied in lymphocyte and mast cells, these kinases are crit...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：
更新日期：2002-08-01 00:00:00
abstract：:Regulation of cell-cell contacts is essential for integrity of the vascular endothelium. Here, a critical role of the F-actin-binding protein drebrin in maintaining endothelial integrity is revealed under conditions mimicking vascular flow. Drebrin knockdown leads to weakening of cell-cell contacts, characterized by l...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.129437
更新日期：2013-08-15 00:00:00
abstract：:Schistosomula of Schistosoma mansoni bind human low density lipoproteins (LDL) in a concentration-dependent and saturable manner. The bound LDL could provide phospholipids and sterol to the worm, which cannot synthesize sterol de novo and lacks acyl chain-modifying capability. Here we have used three phospholipid anal...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1991-05-01 00:00:00
abstract：:The plasma membrane of cells is composed of lateral heterogeneities, patches and microdomains. These membrane microdomains or lipid rafts are enriched in glycosphingolipids and cholesterol and have been implicated in cellular processes such as membrane sorting and signal transduction. In this study we investigated the...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2002-06-15 00:00:00
abstract：:Mastigonemes are hair-like projections on the flagella of various kinds of lower eukaryotes. We obtained a monoclonal antibody (mAb-MAST1) to mastigonemes of Chlamydomonas reinhardtii, and found that it reacts with a single flagellar glycoprotein of about 230 kDa. Interestingly, immunofluorescence microscopy demonstra...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1996-01-01 00:00:00
abstract：:Cadherins are transmembrane glycoproteins involved in Ca2+-dependent cell-cell adhesion. Using L cells expressing one of three functional E-cadherin constructs, the wild-type, a chimeric molecule with alpha-catenin (EalphaC), and a tail-less one, we determined the effect of v-Src expression on E-cadherin-mediated adhe...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2001-02-01 00:00:00
abstract：:hnRNP A1 (34 kDa) is an RNA binding protein consisting of two tandemly arranged RNA binding domains C-terminally linked to a glycine-rich auxiliary domain (2 x RBD-Gly). A1 belongs to the set of polypeptides that bind nascent hnRNA in the nucleus to form the so called hnRNP complexes. These complexes seem to be involv...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-02-01 00:00:00
abstract：:Circadian rhythms exist in most living organisms. The general molecular mechanisms that are used to generate 24-hour rhythms are conserved among organisms, although the details vary. These core clocks consist of multiple regulatory feedback loops, and must be coordinated and orchestrated appropriately for the fine-tun...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.065771
更新日期：2011-02-01 00:00:00
abstract：:We have recently shown that leukotriene D(4) (LTD(4)) increases cell survival in intestinal epithelial cells. Here we report and explore the complementary finding that LTD(4) also enhances proliferation in these cells. This proliferative response was approximately half of that induced by epidermal growth factor (EGF) ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2002-05-01 00:00:00
abstract：:Rac1 and Rac3 are highly homologous regulatory proteins that belong to the small GTPases of the Rho family. Previously, we showed that Rac3 induces cell rounding and prevents neuronal differentiation, in contrast to its close relative Rac1, which stimulates cell spreading and neuritogenesis. To explain these opposing ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.039958
更新日期：2009-06-15 00:00:00
abstract：:When they are fixed with glutaraldehyde in the presence of calcium ions, the plasma membranes of Beroe giant smooth muscle fibres display micropapillae filled with an electron-dense deposit. After freeze-fracturing of fixed tissue, the micropapillae are still present, therefore their shape and size are determined duri...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1982-06-01 00:00:00
abstract：:It is becoming clear that mechanical stimuli are crucial factors in regulating the biology of the cell, but the short-term structural response of a cell to mechanical forces remains relatively poorly understood. We mechanically stimulated cells transiently expressing actin-EGFP with controlled forces (0-20 nN) in orde...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.088302
更新日期：2012-02-01 00:00:00
