21 research outputs found

    The vitamin K-dependent anticoagulant factor, protein S, regulates vascular permeability

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    Protein S (PROS1) is a vitamin K-dependent anticoagulant factor, which also acts as an agonist for the TYRO3, AXL, and MERTK (TAM) tyrosine kinase receptors. PROS1 is produced by the endothelium which also expresses TAM receptors, but little is known about its effects on vascular function and permeability. Transwell permeability assays as well as Western blotting and immunostaining analysis were used to monitor the possible effects of PROS1 on both endothelial cell permeability and on the phosphorylation state of specific signaling proteins. We show that human PROS1, at its circulating concentrations, substantially increases both the basal and VEGFA-induced permeability of endothelial cell (EC) monolayers. PROS1 induces p38 MAPK (Mitogen Activated Protein Kinase), Rho/ROCK (Rho-associated protein kinase) pathway activation, and actin filament remodeling, as well as substantial changes in Vascular Endothelial Cadherin (VEC) distribution and its phosphorylation on Ser665 and Tyr685. It also mediates c-Src and PAK-1 (p21-activated kinase 1) phosphorylation on Tyr416 and Ser144, respectively. Exposure of EC to human PROS1 induces VEC internalization as well as its cleavage into a released fragment of 100 kDa and an intracellular fragment of 35 kDa. Using anti-TAM neutralizing antibodies, we demonstrate that PROS1-induced VEC and c-Src phosphorylation are mediated by both the MERTK and TYRO3 receptors but do not involve the AXL receptor. MERTK and TYRO3 receptors are also responsible for mediating PROS1-induced MLC (Myosin Light Chain) phosphorylation on a site targeted by the Rho/ROCK pathway. Our report provides evidence for the activation of the c-Src/VEC and Rho/ROCK/MLC pathways by PROS1 for the first time and points to a new role for PROS1 as an endogenous vascular permeabilizing factor

    Asymmetric dimethylation of ribosomal S6 kinase 2 regulates its cellular localisation and pro-survival function

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    Ribosomal S6 kinases (S6Ks) are critical regulators of cell growth, homeostasis, and survival, with dysregulation of these kinases found to be associated with various malignancies. While S6K1 has been extensively studied, S6K2 has been neglected despite its clear involvement in cancer progression. Protein arginine methylation is a widespread post-translational modification regulating many biological processes in mammalian cells. Here, we report that p54-S6K2 is asymmetrically dimethylated at Arg-475 and Arg-477, two residues conserved amongst mammalian S6K2s and several AT-hook-containing proteins. We demonstrate that this methylation event results from the association of S6K2 with the methyltransferases PRMT1, PRMT3, and PRMT6 in vitro and in vivo and leads to nuclear the localisation of S6K2 that is essential to the pro-survival effects of this kinase to starvation-induced cell death. Taken together, our findings highlight a novel post-translational modification regulating the function of p54-S6K2 that may be particularly relevant to cancer progression where general Arg-methylation is often elevated

    Search for R-parity violating supersymmetry with displaced vertices in proton-proton collisions at root s=8 TeV

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    Description and performance of track and primary-vertex reconstruction with the CMS tracker

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    A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For tbar t events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of pT > 0.9GeV is 94% for pseudorapidities of |η| < 0.9 and 85% for 0.9 < |η| < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of pT = 100GeV emitted at |η| < 1.4, the resolutions are approximately 2.8% in pT, and respectively, 10μm and 30μm in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10–12μm in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung

    Measurement of the WZ production cross section in pp collisions at root s=7 and 8 TeV and search for anomalous triple gauge couplings at root s=8 TeV

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    Search for long-lived charged particles in proton-proton collisions at root s=13 TeV

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    Measurements of differential and double-differential Drell–Yan cross sections in proton–proton collisions at √s = 8TeV

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    Measurements of the differential and double-differential Drell–Yan cross sections in the dielectron and dimuon channels are presented. They are based on proton–proton collision data at vs = 8TeV recorded with the CMS detector at the LHC and corresponding to an integrated luminosity of 19.7 fb-1. The measured inclusive cross section in the ZZ peak region (60–120 GeV), obtained from the combination of the dielectron and dimuon channels, is 1138±8(exp)±25(theo)±30(lumi)\,pb, where the statistical uncertainty is negligible. The differential cross section ds/dm in the dilepton mass range 15–2000 GeV is measured and corrected to the full phase space. The double-differential cross section d2s/dmd|y| is also measured over the mass range 20 to 1500 GeV and absolute dilepton rapidity from 0 to 2.4. In addition, the ratios of the normalized differential cross sections measured at vs = 7 and 8 TeV are presented. These measurements are compared to the predictions of perturbative QCD at next-to-leading and next-to-next-to-leading (NNLO) orders using various sets of parton distribution functions (PDFs). The results agree with the NNLO theoretical predictions computed with fewz 3.1 using the CT10 NNLO and NNPDF2.1 NNLO PDFs. The measured double-differential cross section and ratio of normalized differential cross sections are sufficiently precise to constrain the proton PDFs.[…] the Secretaría de Estado de Investigación, Desarrollo e Innovación and Programa Consolider-Ingenio 2010, Spain […

    Search for supersymmetry with multiple charged leptons in proton-proton collisions at sqrt(s) = 13 TeV

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    Results are reported from a search for physics beyond-the-standard-model, such as supersymmetry, in final states with at least three charged leptons, in any combination of electrons or muons. The data sample corresponds to an integrated luminosity of 2.3 inverse femtobarns of proton-proton collisions at sqrt(s) = 13 TeV, recorded by the CMS experiment at the LHC in 2015. Two jets are required in each event, providing good sensitivity to strong production of gluinos and squarks. The search regions, sensitive to a range of different supersymmetry scenarios, are defined using the number of jets tagged as originating from bottom quarks, the sum of the magnitudes of the transverse momenta of the jets, the imbalance in the overall transverse momentum in the event, and the invariant mass of opposite-sign, same-flavor lepton pairs. The event yields observed in data are consistent with the expected background contributions from standard model processes. These results are used to derive limits in terms of R-parity conserving simplified models of supersymmetry that describe strong production of gluinos and squarks. Model-independent limits are presented to facilitate the reinterpretation of the results in a broad range of scenarios for physics beyond the standard model

    The catalytic class I(A) PI3K Isoforms play divergent roles in breast cancer cell migration

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    Transforming growth factor-\u3b2 (TGF\u3b2) plays an important role in breast cancer metastasis. Here phosphoinositide 3-kinase (PI3K) signalling was found to play an essential role in the enhanced migration capability of fibroblastoid cells (FibRas) derived from normal mammary epithelial cells (EpH4) by transduction of oncogenic Ras (EpRas) and TGF\u3b21. While expression of the PI3K isoform p110\u3b4 was down-regulated in FibRas cells, there was an increase in the expression of p110\u3b1 and p110\u3b2 in the fibroblastoid cells. The PI3K isoform p110\u3b2 was found to specifically contribute to cell migration in FibRas cells, while p110\u3b1 contributed to the response in EpH4, EpRas and FibRas cells. Akt, a downstream targets of PI3K signalling, had an inhibitory role in the migration of transformed breast cancer cells, while Rac, Cdc42 and the ribosomal protein S6 kinase (S6K) were necessary for the response. Together our data reveal a novel specific function of the PI3K isoform p110\u3b2 in the migration of cells transformed by oncogenic H-Ras and TGF-\u3b2
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