Abstract：
:Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of ccm1 mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the ccm1 mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Lisowska J,Rödel CJ,Manet S,Miroshnikova YA,Boyault C,Planus E,De Mets R,Lee HH,Destaing O,Mertani H,Boulday G,Tournier-Lasserve E,Balland M,Abdelilah-Seyfried S,Albiges-Rizo C,Faurobert Edoi
10.1242/jcs.216093subject
Has Abstractpub_date
2018-08-13 00:00:00issue
15eissn
0021-9533issn
1477-9137pii
jcs.216093journal_volume
131pub_type
杂志文章abstract：:In the present study, to further elucidate the molecular events that control neural crest cell migration, we have analyzed in vitro the adhesive and locomotory response of avian trunk neural crest cells to laminin-1 and searched for the integrin receptors involved in this process. Adhesion of crest cells on laminin-1 ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1997-11-01 00:00:00
abstract：:The glucocorticoid receptor and the mineralocorticoid receptor are hormone-dependent transcription factors. They regulate the excitability of rat hippocampus CA1 neurons in a coordinated fashion. We studied the spatial distribution of these transcription factors in nuclei of CA1 neurons by dual labeling immunocytochem...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1996-04-01 00:00:00
abstract：:Regulation of the localization of mRNAs and local translation are universal features in eukaryotes and contribute to cellular asymmetry and differentiation. In Saccharomyces cerevisiae, localization of mRNAs that encode membrane proteins requires the She protein machinery, including the RNA-binding protein She2p, as w...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.149799
更新日期：2014-08-01 00:00:00
abstract：:Reorganization of the actin cytoskeleton is essential to numerous cellular processes including cell locomotion and cytokinesis. This actin remodeling is regulated in part by Rho family GTPases. Previous studies implicated Trio, a Dbl-homology guanine nucleotide exchange factor with two exchange factor domains, in regu...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2001-01-01 00:00:00
abstract：:Deleted in liver cancer 1 (DLC1) is a multi-modular Rho-GTPase-activating protein (RhoGAP) and a tumor suppressor. Besides its RhoGAP domain, functions of other domains in DLC1 remain largely unknown. By protein precipitation and mass spectrometry, we identified eukaryotic elongation factor 1A1 (EF1A1) as a novel part...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.027482
更新日期：2009-02-01 00:00:00
abstract：:Although the long-term effects of all-trans retinoic acid (RA) on neuronal growth and differentiation have been intensively studied, nothing is known about its effect on synaptic transmission. Here we show that RA rapidly and specifically enhances the spontaneous acetylcholine release at developing neuromuscular synap...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.01153
更新日期：2004-06-15 00:00:00
abstract：:The migration of neutrophils from blood vessels to peripheral tissues is a key step of inflammation. This requires the formation of transient gaps between endothelial cells with concomitant leucocyte squeezing through these narrow apertures and immediate restoration of endothelium continuity. It is currently considere...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1994-09-01 00:00:00
abstract：:A tissue culture system for epithelial cells derived from male human foetal genital ducts has been established. The cells show morphological and biochemical characteristics of ductal epithelial cells, and can be passaged and maintained in culture for considerable periods of time. These cells will provide a suitable sy...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1989-04-01 00:00:00
abstract：:The degradation of misfolded proteins is essential for cellular homeostasis. Misfolded proteins are normally degraded by the ubiquitin-proteasome system (UPS), and selective autophagy serves as a backup mechanism when the UPS is overloaded. Selective autophagy mediates the degradation of harmful material by its seques...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.214304
更新日期：2018-10-04 00:00:00
abstract：:Intracellular membrane fusion occurs with exquisite coordination and specificity. Each fusion event requires three basic components: Rab-GTPases organize the fusion site; SNARE proteins act during fusion; and N-ethylmaleimide-sensitive factor (NSF) plus its cofactor alpha-SNAP are required for recycling or activation ...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.02561
更新日期：2005-09-01 00:00:00
abstract：:The recently identified 63 kDa membrane protein, p63, is a resident protein of a membrane network interposed in between rough ER and Golgi apparatus. To characterize p63 at the molecular level a 2.91 kb cDNA encoding p63 has been isolated from a human placenta lambda gt10 cDNA library. Sequence analysis of tryptic pep...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1993-03-01 00:00:00
abstract：:Cultured human keratinocytes maintained in 30 microM Ca2+ do not form adherens junctions; however, when the extracellular Ca2+ concentration is raised to 1 mM, adherens junctions form very rapidly. The formation of a junction involves the coordinate organization of intracellular and extracellular components. Cadherins...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1994-12-01 00:00:00
abstract：:The formation of cytoplasmic stress granules and the innate immune response are two distinct cellular stress responses. Our study investigated the involvement of four innate immune proteins - retinoic-acid-inducible gene I (RIG-I, also known as DDX58), melanoma differentiation-associated gene 5 (MDA5, also known as IF...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.139626
更新日期：2014-06-01 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：:The tetrapeptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) is a natural regulator of hematopoietic stem cell proliferation. The present study was aimed at investigating the presence and the role of AcSDKP in rat testis. Specific immunoreactivity was always observed in the interstitial tissue at all stages of test...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2000-01-01 00:00:00
abstract：:Small latent TGF-beta consists of latency associated peptide (LAP) bound to the 25 kDa TGF-beta by noncovalent interactions. Small latent TGF-beta is secreted from cells and deposited into the extracellular matrix as covalent complexes with its binding proteins, LTBPs. Four LTBPs have been molecularly cloned and their...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2001-08-01 00:00:00
abstract：:Diversity of cell lineages within glandular organs is generated postnatally by differentiation of committed progenitor cells. Fundamental regulatory aspects of this process are not understood. The mouse submandibular salivary gland (SSG) served as model to assess the role of epidermal growth factor (EGF) receptor sign...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
abstract：:In plants, many nucleus-encoded proteins are targeted to both mitochondria and plastids, and this process is generally mediated by ambiguous N-terminal targeting sequences that are recognized by receptors on both organelles. In many algae, however, plastids were acquired by secondarily engulfing green or red algae, wh...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.116533
更新日期：2012-12-15 00:00:00
abstract：:We have investigated the role in macrophage lysosomal enzyme release of arachidonate metabolites, extracellular divalent cations and cyclic AMP (cAMP) which modulate secretion in other cell types. Lysosomal enzyme secretion induced by zymosan was accompanied by release of malondialdehyde (MDA), which is derived from a...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1980-08-01 00:00:00
abstract：:Arf GTPases regulate both the morphological and protein sorting events that are essential for membrane trafficking. Guanine nucleotide exchange factors (GEFs) specific for Arf proteins determine when and where Arf GTPases will be activated in cells. The yeast Gea2p Arf GEF is a member of an evolutionarily conserved fa...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.00896
更新日期：2004-02-15 00:00:00
abstract：:MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in gene regulation. We have previously reported that activin receptor-like kinase 7 (ALK7) and its ligand, Nodal, induce apoptosis in human epithelial ovarian cancer cells. In this study, we examined the regulation of ALK7 by miRNAs and demonstrate ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.072223
更新日期：2011-02-01 00:00:00
abstract：:The Rho-family proteins make up a major branch of the Ras superfamily of small GTPases. To date, 22 human genes encoding at least 25 proteins have been described. The best known 'classical' members are RhoA, Rac1 and Cdc42. Highly related isoforms of these three proteins have not been studied as intensively, in part b...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.01118
更新日期：2004-03-15 00:00:00
abstract：:Cyclic AMP-dependent protein kinase (cAPK) is the intracellular mediator of signal transduction events involving the adenylate cyclase-cyclic AMP system. A monoclonal antibody (MAb BB1) to the type II regulatory subunit (RII) of cAPK was used in a post-embedding immunogold-labeling procedure to determine the ultrastru...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1989-08-01 00:00:00
abstract：:Microtubules stimulate contractile-ring formation in the equatorial cortex and simultaneously suppress contractility in the polar cortex; how they accomplish these differing activities is incompletely understood. We measured the behavior of GFP-actin in mammalian cells treated with nocodazole under conditions that eit...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.027052
更新日期：2008-07-15 00:00:00
abstract：:Members of the ezrin-radixin-moesin (ERM) family of proteins are involved in multiple aspects of cell migration by acting both as crosslinkers between the membrane, receptors and the actin cytoskeleton, and as regulators of signalling molecules that are implicated in cell adhesion, cell polarity and migration. Increas...
journal_title：Journal of cell science
pub_type： 杂志文章,评审
doi：10.1242/jcs.133108
更新日期：2014-01-15 00:00:00
abstract：:Transcription factor E2F plays an important role in coordinating and integrating early cell cycle progression with the transcription apparatus. It is known that physiological E2F arises when a member of two families of proteins, E2F and DP, interact as E2F/DP heterodimers and that transcriptional activity is regulated...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1997-11-01 00:00:00
abstract：:The tandemly organised ribosomal DNA (rDNA) repeats are transcribed by a dedicated RNA polymerase in a specialised nuclear compartment, the nucleolus. There appears to be an intimate link between the maintenance of nucleolar structure and the presence of heterochromatic chromatin domains. This is particularly evident ...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：2000-12-01 00:00:00
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
doi：10.1242/jcs.006064
更新日期：2008-02-01 00:00:00
abstract：:Cysteine proteases are involved in the degradation of intracellular and extracellular proteins, although their precise roles in vivo are not well understood. Here we characterise a genetic mutant of the Caenorhabditis elegans cathepsin L protease gene cpl-1. CPL-1 is provided maternally and is essential for C. elegans...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：10.1242/jcs.01387
更新日期：2004-10-01 00:00:00
abstract：:Syntaxins are thought to participate in the specific interactions between vesicles and acceptor membranes in intracellular protein trafficking. VAM3 of Saccharomyces cerevisiae encodes a 33 kDa protein (Vam3p) with a hydrophobic transmembrane segment at its C terminus. Vam3p has structural similarities to syntaxins of...
journal_title：Journal of cell science
pub_type： 杂志文章
doi：
更新日期：1997-06-01 00:00:00
