Bosutinib prevents vascular leakage by reducing focal adhesion turnover and reinforcing junctional integrity.


: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.


J Cell Sci


Journal of cell science


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 J




Has Abstract


2020-05-14 00:00:00












  • Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors.

    abstract::Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclea...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Fung TS,Ji WK,Higgs HN,Chakrabarti R

    更新日期:2019-09-23 00:00:00

  • Three-dimensional imaging of living neurons and glia with the atomic force microscope.

    abstract::The atomic force microscope (AFM) was used to directly image hippocampal neurons and glia. Using chemically fixed and living cells it was possible to reconstruct three-dimensional cell structure and detect sub-cellular features such as the nucleus, mitochondria and filaments. By repeatedly scanning a single living cel...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Parpura V,Haydon PG,Henderson E

    更新日期:1993-02-01 00:00:00

  • Experimental toolbox for quantitative evaluation of clathrin-mediated endocytosis in the plant model Arabidopsis.

    abstract::Clathrin-mediated endocytosis (CME) is a crucial cellular process implicated in many aspects of plant growth, development, intra- and intercellular signaling, nutrient uptake and pathogen defense. Despite these significant roles, little is known about the precise molecular details of how CME functions in planta To fac...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Johnson A,Gnyliukh N,Kaufmann WA,Narasimhan M,Vert G,Bednarek SY,Friml J

    更新日期:2020-08-06 00:00:00

  • A molecular link A molecular link between Hairless and Pros26.4, a member of the AAA-ATPase subunits of the proteasome 19S regulatory particle in Drosophila.

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    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Müller D,Nagel AC,Maier D,Preiss A

    更新日期:2006-01-15 00:00:00

  • Effect of isolated plasma membranes on cell cohesion in the cellular slime mould.

    abstract::The effects of isolated plasma membranes on cohesion of Dictyostelium discoideum Ax-2 cells have been studied. Membranes isolated from cells in the log phase of growth gave complete inhibition of log-phase cell cohesion. This effect was specific for the cohesion log-phase cells mediated by contact sites B, since the c...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Jaffé AR,Garrod DR

    更新日期:1979-12-01 00:00:00

  • Novel function of beta-arrestin2 in the nucleus of mature spermatozoa.

    abstract::A growing number of proteins originally found in endocytic structures of the plasma membrane appear to be able to traffic into the nucleus, but the cellular function of this translocation remains unclear. We have found that beta-arrestin2, which typically shows a cytoplasmic localization owing to constitutive nuclear ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Neuhaus EM,Mashukova A,Barbour J,Wolters D,Hatt H

    更新日期:2006-08-01 00:00:00

  • Integrin signal masks growth-promotion activity of HB-EGF in monolayer cell cultures.

    abstract::The extracellular environment and tissue architecture contribute to proper cell function and growth control. Cells growing in monolayers on standard polystyrene tissue culture plates differ in their shape, growth rate and response to external stimuli, compared with cells growing in vivo. Here, we showed that the EGFR ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Mizushima H,Wang X,Miyamoto S,Mekada E

    更新日期:2009-12-01 00:00:00

  • Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links.

    abstract::The events responsible for repair of DNA interstrand cross-links in mammalian cells, the proteins involved and their interactions with each other are poorly understood. The present study demonstrates that the structural protein nonerythroid alpha spectrin (alphaSpIISigma*), present in normal human cell nuclei, plays a...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Sridharan D,Brown M,Lambert WC,McMahon LW,Lambert MW

    更新日期:2003-03-01 00:00:00

  • Isolation and characterization of the Pin1/Ess1p homologue in Schizosaccharomyces pombe.

    abstract::Pin1/Ess1p is a highly conserved WW domain-containing peptidyl-prolyl isomerase (PPIase); its WW domain binds specifically to phospho-Ser/Thr-Pro sequences and its catalytic domain isomerizes phospho-Ser/Thr-Pro bonds. Pin1 PPIase activity can alter protein conformation in a phosphorylation-dependent manner and/or pro...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Huang HK,Forsburg SL,John UP,O'Connell MJ,Hunter T

    更新日期:2001-10-01 00:00:00

  • Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration.

    abstract::Previous reports have suggested that Cx26 exhibits unique intracellular transport pathways en route to the cell surface compared with other members of the connexin family. To directly examine and compare nascent and steady-state delivery of Cx43 and Cx26 to the plasma membrane and gap junction biogenesis we expressed ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Thomas T,Jordan K,Simek J,Shao Q,Jedeszko C,Walton P,Laird DW

    更新日期:2005-10-01 00:00:00

  • Ca2+ influx and protein scaffolding via TRPC3 sustain PKCbeta and ERK activation in B cells.

    abstract::Ca(2+) signaling mediated by phospholipase C that produces inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] and diacylglycerol (DAG) controls lymphocyte activation. In contrast to store-operated Ca(2+) entry activated by Ins(1,4,5)P(3)-induced Ca(2+) release from endoplasmic reticulum, the importance of DAG-activated Ca(...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Numaga T,Nishida M,Kiyonaka S,Kato K,Katano M,Mori E,Kurosaki T,Inoue R,Hikida M,Putney JW Jr,Mori Y

    更新日期:2010-03-15 00:00:00

  • A model suite of green algae within the Scenedesmaceae for investigating contrasting desiccation tolerance and morphology.

    abstract::Microscopic green algae inhabiting desert microbiotic crusts are remarkably diverse phylogenetically, and many desert lineages have independently evolved from aquatic ancestors. Here we worked with five desert and aquatic species within the family Scenedesmaceae to examine mechanisms that underlie desiccation toleranc...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Cardon ZG,Peredo EL,Dohnalkova AC,Gershone HL,Bezanilla M

    更新日期:2018-04-10 00:00:00

  • Vinculin but not alpha-actinin is a target of PKC phosphorylation during junctional assembly induced by calcium.

    abstract::The establishment of the junctional complex in epithelial cells requires the presence of extracellular calcium, and is controlled by a network of reactions involving G-proteins, phospholipase C and protein kinase C. Since potential candidates for phosphorylation are the tight junction associated proteins ZO1, ZO2 and ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Perez-Moreno M,Avila A,Islas S,Sanchez S,González-Mariscal L

    更新日期:1998-12-01 00:00:00

  • A synthetic promoter for multi-stage expression to probe complementary functions of Plasmodium adhesins.

    abstract::Gene expression of malaria parasites is mediated by the apicomplexan Apetala2 (ApiAP2) transcription factor family. Different ApiAP2s control gene expression at distinct stages in the complex life cycle of the parasite, ensuring timely expression of stage-specific genes. ApiAP2s recognize short cis-regulatory elements...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Klug D,Kehrer J,Frischknecht F,Singer M

    更新日期:2018-10-22 00:00:00

  • Probing the free space within rat and chicken chromatin with active and passive probes.

    abstract::The cavity systems within chicken erythrocyte nuclei and rat liver nuclei were compared using passive probes of radioactive glycogen and active probes of nuclease-armed-glycogen. The passive probe curves have a form that indicates that they are due to passive occupation of spaces and not due to the effects of a limiti...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Burgoyne LA,Skinner JD

    更新日期:1979-06-01 00:00:00

  • Constitutive activity of the Ghrelin receptor reduces surface expression of voltage-gated Ca2+ channels in a CaVβ-dependent manner.

    abstract::Voltage-gated Ca2+ (CaV) channels couple membrane depolarization to Ca2+ influx, triggering a range of Ca2+-dependent cellular processes. CaV channels are, therefore, crucial in shaping neuronal activity and function, depending on their individual temporal and spatial properties. Furthermore, many neurotransmitters an...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Mustafá ER,López Soto EJ,Martínez Damonte V,Rodríguez SS,Lipscombe D,Raingo J

    更新日期:2017-11-15 00:00:00

  • The nuclear protein Waharan is required for endosomal-lysosomal trafficking in Drosophila.

    abstract::Here we report Drosophila Waharan (Wah), a 170-kD predominantly nuclear protein with two potential human homologues, as a newly identified regulator of endosomal trafficking. Wah is required for neuromuscular-junction development and muscle integrity. In muscles, knockdown of Wah caused novel accumulations of tightly ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Lone M,Kungl T,Koper A,Bottenberg W,Kammerer R,Klein M,Sweeney ST,Auburn RP,O'Kane CJ,Prokop A

    更新日期:2010-07-15 00:00:00

  • Extracellular matrix dynamics in development and regenerative medicine.

    abstract::The extracellular matrix (ECM) regulates cell behavior by influencing cell proliferation, survival, shape, migration and differentiation. Far from being a static structure, the ECM is constantly undergoing remodeling--i.e. assembly and degradation--particularly during the normal processes of development, differentiati...

    journal_title:Journal of cell science

    pub_type: 杂志文章,评审


    authors: Daley WP,Peters SB,Larsen M

    更新日期:2008-02-01 00:00:00

  • MOR1, the Arabidopsis thaliana homologue of Xenopus MAP215, promotes rapid growth and shrinkage, and suppresses the pausing of microtubules in vivo.

    abstract::MOR1, the Arabidopsis thaliana homologue of the Xenopus microtubule-associated protein MAP215, is required for spatial organization of the acentrosomal microtubule arrays of plant cells. To determine how loss of MOR1 function affects microtubule dynamics, we compared various parameters of microtubule dynamics in the t...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Kawamura E,Wasteneys GO

    更新日期:2008-12-15 00:00:00

  • Events in the cytoplasm during male meiosis in Lilium.

    abstract::An electron microscopic investigation of the events associated with meiosis in Lilium has revealed a number of changes in both the organellar population and the other cytoplasmic components. Ribosome numbers decrease significantly in early prophase and are later replenished in the tetrads, a process most likely involv...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Bird J,Porter EK,Dickinson HG

    更新日期:1983-01-01 00:00:00

  • Cytostellin distributes to nuclear regions enriched with splicing factors.

    abstract::Cytostellin, a approximately 240 kDa phosphoprotein found in all cells examined from human to yeast, is predominantly intranuclear in interphase mammalian cells and undergoes continuous redistribution during the cell cycle. Here, mammalian cytostellin is shown to localize to intranuclear regions enriched with multiple...

    journal_title:Journal of cell science

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    authors: Bregman DB,Du L,Li Y,Ribisi S,Warren SL

    更新日期:1994-03-01 00:00:00

  • Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors.

    abstract::Brain-derived neurotrophic factor (BDNF) is encoded by multiple mRNA variants whose differential subcellular distribution constitutes a 'spatial code' for local translation of BDNF and selective morphological remodeling of dendrites. Here, we investigated where BDNF translation takes place and what are the signaling p...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Baj G,Pinhero V,Vaghi V,Tongiorgi E

    更新日期:2016-07-15 00:00:00

  • Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF.

    abstract::Hepatocyte growth factor, also known as scatter factor, is a pleiotropic cytokine, which stimulates cell motility, invasion, proliferation, survival and morphogenesis, and induces the expression of specific genes by activating its receptor tyrosine kinase. In this work we have isolated, characterized and used as agoni...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Prat M,Crepaldi T,Pennacchietti S,Bussolino F,Comoglio PM

    更新日期:1998-01-01 00:00:00

  • A nuclear localization signal can enhance both the nuclear transport and expression of 1 kb DNA.

    abstract::Although the entry of DNA into the nucleus is a crucial step of non-viral gene delivery, fundamental features of this transport process have remained unexplored. This study analyzed the effect of linear double stranded DNA size on its passive diffusion, its active transport and its NLS-assisted transport. The size lim...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Ludtke JJ,Zhang G,Sebestyén MG,Wolff JA

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  • Chlamydomonas DIP13 and human NA14: a new class of proteins associated with microtubule structures is involved in cell division.

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    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Pfannenschmid F,Wimmer VC,Rios RM,Geimer S,Kröckel U,Leiherer A,Haller K,Nemcová Y,Mages W

    更新日期:2003-04-15 00:00:00

  • Nutrient regulation of mTORC1 at a glance.

    abstract::The mechanistic target of rapamycin (mTOR) signaling pathway coordinates environmental and intracellular cues to control eukaryotic cell growth. As a pivot point between anabolic and catabolic processes, mTOR complex 1 (mTORC1) signaling has established roles in regulating metabolism, translation and autophagy. Hypera...

    journal_title:Journal of cell science

    pub_type: 杂志文章,评审


    authors: Condon KJ,Sabatini DM

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    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Harper CV,Cummerson JA,White MR,Publicover SJ,Johnson PM

    更新日期:2008-07-01 00:00:00

  • Frustration of endocytosis potentiates compression-induced receptor signaling.

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    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Baschieri F,Le Devedec D,Tettarasar S,Elkhatib N,Montagnac G

    更新日期:2020-09-01 00:00:00

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    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Gonçalves AP,Cordeiro JM,Monteiro J,Muñoz A,Correia-de-Sá P,Read ND,Videira A

    更新日期:2014-09-01 00:00:00

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    abstract::Rapid endocytosis of lipoprotein receptors involves NPxY signals contained in their cytoplasmic tails. Several proteins, including ARH and Dab2, can bind these sequences, but their importance for endocytosis may vary in different cell types. The lipoprotein receptor megalin is expressed in the visceral endoderm (VE), ...

    journal_title:Journal of cell science

    pub_type: 杂志文章


    authors: Maurer ME,Cooper JA

    更新日期:2005-11-15 00:00:00