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：: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
abstract：:Postsynaptic neuronal dendrites undergo functional and morphological changes in response to pathologically excessive synaptic activation. Although rapid formation of segmental focal swelling (varicosity) is the most prominent hallmark in such excitotoxic injury, little is known about the pathophysiological function of...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2001-11-01 00:00:00
abstract：:Efficient trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) to and from the cell surface is essential for maintaining channel density at the plasma membrane (PM) and ensuring proper physiological activity. The most common mutation, F508del, exhibits reduced surface expression and impaired f...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.120196
更新日期：2013-06-15 00:00:00
abstract：:The pericentriolar recycling endosome (RE) may be an alternative compartment through which some beta2-adrenergic receptors (beta2ARs) recycle from early endosomes to the cell surface during prolonged exposure to agonist. For the transferrin receptor, CXCR2, and the M4-muscarinic acetylcholine receptor, trafficking thr...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.01168
更新日期：2004-07-01 00:00:00
abstract：:Expression of the vitronectin gene was detected in advanced human astrocytoma by in situ hybridization, whereas vitronectin mRNA was undetectable in low grade tumors or in normal adult brain, indicating that vitronectin is a marker of malignant astrocytoma. We established a model of human astrocytoma by transplanting ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:Loss of tissue organization is a hallmark of the early stages of cancer, and there is considerable interest in proteins that maintain normal tissue architecture. Prostate epithelial cells cultured in Matrigel form three-dimensional acini that mimic aspects of prostate gland development. The organization of these struc...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.119388
更新日期：2013-04-15 00:00:00
abstract：:Using a polyclonal antibody against purified zymogen granule membrane components from rat pancreas a cDNA coding for the 29 kDa protein (ZG29p) was identified by immunoscreening of a hormonally stimulated pancreas cDNA library. Western blot analysis suggests that ZG29p is a pancreas-specific protein and immunofluoresc...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1999-08-01 00:00:00
abstract：:Neutrophil extracellular traps (NETs) are one of the most intriguing discoveries in immunological research of the past few years. After their first description in 2004, the number of research articles on how NETs affect immunodefense, and also how they contribute to an ever-growing number of diseases, has skyrocketed....
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.241075
更新日期：2020-03-10 00:00:00
abstract：:The mechanism by which glutamate regulates the cytosolic free Ca2+ concentration ([Ca2+]c) in spontaneously firing dopamine neurons is not clear. Thus we have investigated the glutamate-mediated [Ca2+]c dynamics in the acutely isolated dopamine neurons from the rat substantia nigra pars compacta by measuring [Ca2+]c a...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00481
更新日期：2003-07-01 00:00:00
abstract：:Intermediate filament protein keratin 8 (K8) binds to heat shock protein 70 (Hsp70) and p38 MAPK, and is phosphorylated at Ser74 by p38α (MAPK14, hereafter p38). However, a p38 binding site on K8 and the molecular mechanism of K8-p38 interaction related to Hsp70 are unknown. Here, we identify a p38 docking site on K8 ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.229534
更新日期：2019-09-26 00:00:00
abstract：:Basonuclin is a zinc finger protein mainly expressed in keratinocytes of the basal layer of epidermis and the outer root sheath of hair follicles. It is also found in abundance in the germ cells of testis and ovary. In cultured keratinocytes, basonuclin is associated with chromatin in all phases of the cell cycle, inc...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1999-09-01 00:00:00
abstract：:The fractionation of human liver mitochondria into inner membrane, outer membrane and matrix material is reported. Compared with rat, human liver mitochondria are more fragile. Fractionation can be achieved in only 2 steps, a digitonin treatment for removal of the outer membrane and centrifugation of the inner membran...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1979-02-01 00:00:00
abstract：:The movement of cells in small groups, or clusters, was studied in vitro using epithelioid cells from Gordon-Kosswig melanomas (from poecelid fish) and time-lapse cinemicrography. Tumour explants cultured on glass yield cell sheets from which groups of cells separate and become independently motile clusters. These clu...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1981-06-01 00:00:00
abstract：:Start is the main decision point in the eukaryotic cell cycle at which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional programme through the inactivation of Start transcriptional repressors: the retinoblastoma family in mammals, or Whi5 and its recently identi...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.251413
更新日期：2020-12-21 00:00:00
abstract：:A scanning electron-microscope study has established that there are major modifications in the surface membranes of malignant cells transformed from the pronephric kidney of the frog. Tumours were induced in vivo after exposure of embryos Lucké Herpes virus. A pronephric cell line from normal embryos and 3 tumour cell...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1976-11-01 00:00:00
abstract：:Clathrin-mediated endocytosis requires cargo-specific adaptor proteins that recognize specific receptors and recruit them into coated pits. ARH [also called low-density lipoprotein receptor (LDLR) adaptor protein] serves as an adaptor for LDLR endocytosis in liver. However, ARH is dispensable for LDL uptake by some ot...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.03217
更新日期：2006-10-15 00:00:00
abstract：:The presence of an acetolysis-resistant polymer (sporopollenin) in the cellular slime moulds is demonstrated. This polymer is located on the stalk sheath of fruiting bodies as a bundle of fine fibrils (4-5 nm diameter). The location and structure of sporopollenin in spores are shown to vary considerably, depending upo...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1984-03-01 00:00:00
abstract：:Notwithstanding the fact that adult bone marrow cell engraftment to epithelial organs seems a somewhat uncommon event, there is no doubt it does occur, and under appropriate conditions of a strong and positive selection pressure these cells will expand clonally and make a significant contribution to tissue replacement...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.00269
更新日期：2003-02-15 00:00:00
abstract：:This project examines the transcellular membrane protein polarity of bovine aortic endothelial cell (BAEC) monolayers in vitro with respect to the roles that intercellular junctions (as defined by comparing confluent and subconfluent monolayers) and the submembranous cytoskeleton play in controlling this phenomenon. P...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1992-09-01 00:00:00
abstract：:Vertebrate tropomyosins (TMs) are expressed from four genes, and at least 18 distinct isoforms are generated via a complex pattern of alternative RNA splicing and alternative promoters. The functional significance of this isoform diversity is largely unknown and it remains to be determined whether specific isoforms ar...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1999-02-01 00:00:00
abstract：:Sorting nexins are a large family of phox-homology-domain-containing proteins that have been implicated in the control of endosomal sorting. Sorting nexin-1 is a component of the mammalian retromer complex that regulates retrieval of the cation-independent mannose 6-phosphate receptor from endosomes to the trans-Golgi...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.02568
更新日期：2005-10-01 00:00:00
abstract：:Structures retaining many of the morphological features of nuclei may be released by gently lysing human cells in solutions containing non-ionic detergents and high concentrations of salt. These nucleoids contain superhelical DNA. Using a double-labelling procedure we have compared, at different salt concentrations, t...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1978-02-01 00:00:00
abstract：:Nearly all intermediate filament (IF) proteins share two sequence motifs located at the N- and the C-terminal ends of their helical rod domain ('coil 1a' and 'coil 2b', respectively). To examine the structural role of the coil 2b motif, we have performed in vitro assembly studies and in vivo microinjection experiments...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1992-05-01 00:00:00
abstract：:The cloned, SV40-immortalized mouse macrophage cell line, BAC1.2F5, resembles primary macrophages in its dependence on colony-stimulating factor-1 (CSF-1) for both viability and proliferation. Re-addition of CSF-1 stimulates rapid, transient behavioural changes in starved cells, which are rounded, with diffusely organ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1989-07-01 00:00:00
abstract：:Cutaneous wound healing is accelerated by exogenous mechanical forces and is impaired in TRPC6-knockout mice. Therefore, we designed experiments to determine how mechanical force and TRPC6 channels contribute to wound healing using HaCaT keratinocytes. HaCaT cells were pretreated with hyperforin, a major component of ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.147314
更新日期：2014-10-01 00:00:00
abstract：:For all eukaryotic cilia the basal bodies provide a template for the assembly of the doublet microtubules, and intraflagellar transport provides a mechanism for transport of axonemal components into the growing cilium. What is not known is how the central pair of microtubules is nucleated or how their associated polyp...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.096941
更新日期：2012-07-15 00:00:00
abstract：:We have identified and characterized two proteins in rat brain that bind to the neuron-specific tropomyosin isoform, TMBr3. The two proteins were identified by blot overlay assay, in which the proteins immobilized on the membrane were probed by epitope-tagged TMBr3, followed by detection with anti-epitope antibody. We...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1996-09-01 00:00:00
abstract：:AMP-activated protein kinase (AMPK), a cellular metabolic sensor, is essential in energy regulation and metabolism. Hepatocyte polarization during liver development and regeneration parallels increased metabolism. The current study investigates the effects of AMPK and its upstream activator LKB1 on polarity and bile c...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.068098
更新日期：2010-10-01 00:00:00
abstract：:Asymmetric cell division can produce daughter cells with different developmental fates and is often accompanied by a difference in cell size. A number of recent genetic and in vivo imaging studies in Drosophila and Caenorhabditis elegans have begun to elucidate the mechanisms underlying the rearrangements of the cytos...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：
更新日期：2002-06-01 00:00:00
abstract：:Little is known of the molecular basis for the diversity of microtubule structure and function found within the eukaryotic flagellum. Antibodies that discriminate between tyrosinated alpha tubulin and post-translationally detyrosinated alpha tubulin were used to localize these complementary tubulin isoforms in flagell...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1998-02-01 00:00:00
