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https://www.readbyqxmd.com/read/27663674/human-caldag-gefi-deficiency-confers-severe-bleeding-tendency-and-delayed-%C3%AE-iib%C3%AE-3-activation-velocity
#1
Hisashi Kato, Yozo Nakazawa, Yumi Kurokawa, Hirokazu Kashiwagi, Yoichiro Morikawa, Daisuke Morita, Fumiaki Banno, Shigenori Honda, Yuzuru Kanakura, Yoshiaki Tomiyama
Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1 activating molecule and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency...
September 23, 2016: Blood
https://www.readbyqxmd.com/read/27587867/inherited-caldag-gefi-deficiency
#2
Marco Cattaneo
No abstract text is available yet for this article.
September 1, 2016: Blood
https://www.readbyqxmd.com/read/27417588/mice-expressing-low-levels-of-caldag-gefi-exhibit-markedly-impaired-platelet-activation-with-minor-impact-on-hemostasis
#3
Raymond Piatt, David S Paul, Robert H Lee, Steven E McKenzie, Leslie V Parise, Dale O Cowley, Brian C Cooley, Wolfgang Bergmeier
OBJECTIVE: The tight regulation of platelet adhesiveness, mediated by the αIIbβ3 integrin, is critical for hemostasis and prevention of thrombosis. We recently demonstrated that integrin affinity in platelets is controlled by the guanine nucleotide exchange factor, CalDAG-GEFI (CD-GEFI), and its target, RAP1. In this study, we investigated whether low-level expression of CD-GEFI leads to protection from thrombosis without pathological bleeding in mice. APPROACH AND RESULTS: Cdg1(low) mice were generated by knockin of human CD-GEFI cDNA into the mouse Cdg1 locus...
September 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27235139/gdf-15-inhibits-integrin-activation-and-mouse-neutrophil-recruitment-through-the-alk-5-tgf-%C3%AE-rii-heterodimer
#4
Annette Artz, Stefan Butz, Dietmar Vestweber
Growth differentiation factor 15 (GDF-15) is the first cytokine known to counteract chemokine-induced activation of leukocyte integrins. We showed recently that this activity dampens neutrophil recruitment into inflamed tissue and is required for survival of myocardial infarction in mice. The receptor responsible for this GDF-15-triggered anti-inflammatory mechanism on myeloid cells is not known. Here, we identify this receptor as transforming growth factor β receptor I (TGF-βRI) (activin receptor-like kinase 5 [ALK-5]) and TGF-β receptor II (TGF-βRII)...
July 28, 2016: Blood
https://www.readbyqxmd.com/read/27235135/novel-mutations-in-rasgrp2-which-encodes-caldag-gefi-abrogate-rap1-activation-causing-platelet-dysfunction
#5
María Luisa Lozano, Aaron Cook, José María Bastida, David S Paul, Gemma Iruin, Ana Rosa Cid, Rosa Adan-Pedroso, José Ramón González-Porras, Jesús María Hernández-Rivas, Sarah J Fletcher, Ben Johnson, Neil Morgan, Francisca Ferrer-Marin, Vicente Vicente, John Sondek, Steve P Watson, Wolfgang Bergmeier, José Rivera
In addition to mutations in ITG2B or ITGB3 genes that cause defective αIIbβ3 expression and/or function in Glanzmann's thrombasthenia patients, platelet dysfunction can be a result of genetic variability in proteins that mediate inside-out activation of αIIbβ3 The RASGRP2 gene is strongly expressed in platelets and neutrophils, where its encoded protein CalDAG-GEFI facilitates the activation of Rap1 and subsequent activation of integrins. We used next-generation sequencing (NGS) and whole-exome sequencing (WES) to identify 2 novel function-disrupting mutations in RASGRP2 that account for bleeding diathesis and platelet dysfunction in 2 unrelated families...
September 1, 2016: Blood
https://www.readbyqxmd.com/read/27037855/basset-hound-thrombopathia-in-a-4-month-old-female-ba-shar-sharp-asset
#6
Pete W Christopherson, Eric A Alexander, Kevin B King, Mary K Boudreaux
A 3-month-old female Basset Hound-Shar Pei mix puppy (Ba-Shar or Sharp Asset) presented with oral bleeding due to a cracked molar. On physical exam, an aural hematoma was also noted that the owner indicated was chronic. The puppy was hospitalized for over 24 h until the bleeding was brought under control. At 4 months of age, the puppy again presented with oral bleeding due to loss of deciduous teeth and was hospitalized until bleeding was controlled. Coagulation screening tests, platelet numbers, and von Willebrand Factor antigen levels were within reference limits...
June 2016: Veterinary Clinical Pathology
https://www.readbyqxmd.com/read/26988592/caldag-gefi-deficiency-reduces-atherosclerotic-lesion-development-in-mice
#7
Yacine Boulaftali, A Phillip Owens, Ashley Beale, Raymond Piatt, Caterina Casari, Robert H Lee, Pamela B Conley, David S Paul, Nigel Mackman, Wolfgang Bergmeier
OBJECTIVE: Platelets are important for the development and progression of atherosclerotic lesions. However, relatively little is known about the contribution of platelet signaling to this pathological process. Our recent work identified 2 independent, yet synergistic, signaling pathways that lead to the activation of the small GTPase Rap1; one mediated by the guanine nucleotide exchange factor, CalDAG-GEFI (CDGI), the other by P2Y12, a platelet receptor for adenosine diphosphate and the target of antiplatelet drugs...
May 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/26423530/rap1-gtpase-signaling-and-platelet-function
#8
REVIEW
Lucia Stefanini, Wolfgang Bergmeier
Platelets are critical for hemostasis, i.e., the body's ability to prevent blood loss at sites of vascular injury. They patrol the vasculature in a quiescent, non-adhesive state for approximately 10 days, after which they are removed from circulation by phagocytic cells of the reticulo-endothelial system. At sites of vascular injury, they promptly shift to an activated, adhesive state required for the formation of a hemostatic plug. The small GTPase RAP1 is a critical regulator of platelet adhesiveness. Our recent studies demonstrate that the antagonistic balance between the RAP1 regulators, CalDAG-GEFI and RASA3, is critical for the modulation of platelet adhesiveness, both in circulation and at sites of vascular injury...
January 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/26164464/update-on-the-inherited-platelet-disorders
#9
REVIEW
Michele P Lambert
PURPOSE OF REVIEW: The inherited platelet disorders have witnessed a surge in our understanding of molecular mechanisms of disease in the past few years due in large to part to the introduction of next-generation sequencing for discovery of novel genes. The purpose of this review is to update the reader on the novel discoveries with regard to the inherited platelet disorders, with a particular focus on describing the novel disorders described most recently. RECENT FINDINGS: The description of novel mechanisms of disease including mutations in PRKACG, in a family with severe macrothrombocytopenia, RUNX1 and FLI1 mutations in patients with inherited mild platelet function disorders and CalDAG-GEFI resulting in a severe platelet bleeding phenotype show that there is still much to be learned from studying families and molecular sequencing of patients with well phenotyped platelet disorders...
September 2015: Current Opinion in Hematology
https://www.readbyqxmd.com/read/26149024/inherited-disorders-of-platelet-function-selected-updates
#10
REVIEW
A T Nurden, P Nurden
The gene variants responsible for the primary genotype of many platelet disorders have now been identified. Next-generation sequencing technology (NGST), mainly exome sequencing, has highlighted genes responsible for defects in platelet secretion (NBEAL2, gray platelet syndrome), procoagulant activity (STIM1, Stormorken syndrome), and activation pathways (RASGRP2, CalDAG-GEFI deficiency and integrin dysfunction; PRKACG, cyclic adenosine monophosphate-dependent protein kinase deficiency). Often disorders of platelet function are associated with a modified platelet production with changes in platelet number and size and can accompany malfunction of other organs or tissues...
June 2015: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/25705885/rasa3-is-a-critical-inhibitor-of-rap1-dependent-platelet-activation
#11
Lucia Stefanini, David S Paul, Raymond F Robledo, E Ricky Chan, Todd M Getz, Robert A Campbell, Daniel O Kechele, Caterina Casari, Raymond Piatt, Kathleen M Caron, Nigel Mackman, Andrew S Weyrich, Matthew C Parrott, Yacine Boulaftali, Mark D Adams, Luanne L Peters, Wolfgang Bergmeier
The small GTPase RAP1 is critical for platelet activation and thrombus formation. RAP1 activity in platelets is controlled by the GEF CalDAG-GEFI and an unknown regulator that operates downstream of the adenosine diphosphate (ADP) receptor, P2Y12, a target of antithrombotic therapy. Here, we provide evidence that the GAP, RASA3, inhibits platelet activation and provides a link between P2Y12 and activation of the RAP1 signaling pathway. In mice, reduced expression of RASA3 led to premature platelet activation and markedly reduced the life span of circulating platelets...
April 2015: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/25451646/cll2-1-a-chemical-derivative-of-orchid-1-4-phenanthrenequinones-inhibits-human-platelet-aggregation-through-thiol-modification-of-calcium-diacylglycerol-guanine-nucleotide-exchange-factor-i-caldag-gefi
#12
Chieh-Yu Liao, Chia-Lin Lee, Hui-Chun Wang, Shih-Shin Liang, Po-Hsiung Kung, Yang-Chang Wu, Fang-Rong Chang, Chin-Chung Wu
CalDAG-GEFI is a guanine nucleotide exchange factor, which actives small GTPase Rap1 and plays an important role in platelet aggregation. Our previous study has shown that CalDAG-GEFI contains redox-sensitive thiols, and its function can be inhibited by thiol modification. In the present study, the effect of CLL2-1, a 1,4-phenanthrenequinone, on CalDAG-GEFI and platelet functions was investigated. In human platelets, CLL2-1 prevented platelet aggregation caused by various stimulators. Flow cytometric analysis revealed that CLL2-1 inhibited GPIIb/IIIa activation and P-selectin secretion...
January 2015: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/25287077/caldag-gefi-deficiency-protects-mice-from-fc%C3%AE-riia-mediated-thrombotic-thrombocytopenia-induced-by-cd40l-and-%C3%AE-2gpi-immune-complexes
#13
A Amirkhosravi, Y Boulaftali, L Robles-Carrillo, T Meyer, S E McKenzie, J L Francis, W Bergmeier
INTRODUCTION: Platelet activation via the Fcγ receptor IIa (FcγRIIa) is implicated in the pathogenesis of immune complex (IC)-mediated thrombocytopenia and thrombosis (ITT). We previously showed that ICs composed of antigen and antibodies targeting CD40 ligand (CD40L) or β2 Glycoprotein I (β2GPI) induce ITT in mice transgenic for human FcγRIIa (hFcR) but not wild-type controls (which lack FcγRIIa). Here we evaluated the contribution of the guanine nucleotide exchange factor, CalDAG-GEFI, and P2Y12, key regulators of Rap1 signaling in platelets, to ITT induced by these clinically relevant ICs...
December 2014: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/25100610/mechanisms-of-interferon-%C3%AE-production-by-neutrophils-and-its-function-during-streptococcus-pneumoniae-pneumonia
#14
John C Gomez, Mitsuhiro Yamada, Jessica R Martin, Hong Dang, W June Brickey, Wolfgang Bergmeier, Mary C Dinauer, Claire M Doerschuk
Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-γ early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-γ regulates bacterial clearance...
March 2015: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/24980744/identification-of-a-severe-bleeding-disorder-in-humans-caused-by-a-mutation-in-caldag-gefi
#15
COMMENT
William A Muller
No abstract text is available yet for this article.
June 30, 2014: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/24958846/human-caldag-gefi-gene-rasgrp2-mutation-affects-platelet-function-and-causes-severe-bleeding
#16
Matthias Canault, Dorsaf Ghalloussi, Charlotte Grosdidier, Marie Guinier, Claire Perret, Nadjim Chelghoum, Marine Germain, Hana Raslova, Franck Peiretti, Pierre E Morange, Noemie Saut, Xavier Pillois, Alan T Nurden, François Cambien, Anne Pierres, Timo K van den Berg, Taco W Kuijpers, Marie-Christine Alessi, David-Alexandre Tregouet
The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation...
June 30, 2014: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/24829201/trisomy-12-chronic-lymphocytic-leukemia-cells-exhibit-upregulation-of-integrin-signaling-that-is-modulated-by-notch1-mutations
#17
John C Riches, Conor J O'Donovan, Sarah J Kingdon, Fabienne McClanahan, Andrew J Clear, Donna S Neuberg, Lillian Werner, Carlo M Croce, Alan G Ramsay, Laura Z Rassenti, Thomas J Kipps, John G Gribben
The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323...
June 26, 2014: Blood
https://www.readbyqxmd.com/read/24352565/identification-of-caldag-gefi-as-an-intracellular-target-for-the-vicinal-dithiol-binding-agent-phenylarsine-oxide-in-human-platelets
#18
Chih-Yun Kuo, Hui-Chun Wang, Po-Hsiung Kung, Chi-Yu Lu, Chieh-Yu Liao, Ming-Tsang Wu, Chin-Chung Wu
CalDAG-GEFI, a guanine nucleotide exchange factor activating Rap1, is known to play a key role in Ca2+-dependent glycoprotein (GP)IIb/IIIa activation and platelet aggregation. Although inhibition of CalDAG-GEFI could be a potential strategy for antiplatelet therapy, no inhibitor of this protein has been identified. In the present study, phenylarsine oxide (PAO), a vicinal dithiol blocker, potently prevented Rap1 activation in thrombin-stimulated human platelets without significantly inhibiting intracellular Ca2+ mobilisation and protein kinase C activation...
May 5, 2014: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/23611601/phosphorylation-of-caldag-gefi-by-protein-kinase-a-prevents-rap1b-activation
#19
H Subramanian, R P Zahedi, A Sickmann, U Walter, S Gambaryan
BACKGROUND: Signaling via protein kinase A (PKA) and protein kinase G (PKG) is critical for maintaining platelets in the resting state. Both kinases down-regulate the activity of the small GTPase Rap1b, a critical signaling switch for integrin activation and platelet aggregation. However, the mechanism of Rap1b regulation by PKA and PKG is largely unknown. OBJECTIVE: To identify the PKA phosphorylation sites in calcium and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), the main GEF for Rap1b in platelets, and the effect of CalDAG-GEFI phosphorylation in Rap1b activation...
August 2013: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/23600630/phosphorylation-of-the-guanine-nucleotide-exchange-factor-caldag-gefi-by-protein-kinase-a-regulates-ca-2-dependent-activation-of-platelet-rap1b-gtpase
#20
Gianni Francesco Guidetti, Daria Manganaro, Alessandra Consonni, Ilaria Canobbio, Cesare Balduini, Mauro Torti
In blood platelets the small GTPase Rap1b is activated by cytosolic Ca2+ and promotes integrin αIIbβ3 inside-out activation and platelet aggregation. cAMP is the major inhibitor of platelet function and antagonizes Rap1b stimulation through a mechanism that remains unclear. In the present study we demonstrate that the Ca2+-dependent exchange factor for Rap1b, CalDAG-GEFI (calcium and diacylglycerol-regulated guanine-nucleotide-exchange factor I), is a novel substrate for the cAMP-activated PKA (protein kinase A)...
July 1, 2013: Biochemical Journal
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