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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
M Aebi, N Wiedemar, C Drögemüller, R Zanolari
During the years 2012 to 2014, a total of 5 affected Simmental cattle showing persistent bleeding after minor or unknown trauma, were presented at the Clinic for Ruminants or at the Institute for Genetics of the Vetsuisse-Faculty, University of Berne. The homozygous mutation RASGRP2, initially reported in 2007, was present in all these cases and all available parents were heterozygous carriers thus confirming the recessive mode of inheritance. Three affected animals died as a result of persistent bleeding. One animal was stabilized at the Clinic for Ruminants and was slaughtered one month later...
February 2016: Schweizer Archiv Für Tierheilkunde
Jinqi Ren, Aaron A Cook, Wolfgang Bergmeier, John Sondek
The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition...
May 20, 2016: Biochemical and Biophysical Research Communications
Agnes Czikora, Daniel J Lundberg, Adelle Abramovitz, Nancy E Lewin, Noemi Kedei, Megan L Peach, Xiaoling Zhou, Raymond C Merritt, Elizabeth A Craft, Derek C Braun, Peter M Blumberg
The C1 domain represents the recognition module for diacylglycerol and phorbol esters in protein kinase C, Ras guanine nucleotide releasing protein (RasGRP), and related proteins. RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (Kd = 2890 ± 240 nm for [(3)H]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn(7), Ser(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1/3 (Thr(7), Tyr(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (Kd = 1...
May 20, 2016: Journal of Biological Chemistry
Taku Nagai, Shinichi Nakamuta, Keisuke Kuroda, Sakura Nakauchi, Tomoki Nishioka, Tetsuya Takano, Xinjian Zhang, Daisuke Tsuboi, Yasuhiro Funahashi, Takashi Nakano, Junichiro Yoshimoto, Kenta Kobayashi, Motokazu Uchigashima, Masahiko Watanabe, Masami Miura, Akinori Nishi, Kazuto Kobayashi, Kiyofumi Yamada, Mutsuki Amano, Kozo Kaibuchi
Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1...
February 3, 2016: Neuron
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
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
Junichi Takino, Kentaro Nagamine, Takamitsu Hori
Ras guanyl nucleotide releasing proteins (RasGRPs) are guanine nucleotide exchange factors that activate Ras and Rap. We recently reported that xrasgrp2, which is a homolog of the human rasgrp2, plays a role in vasculogenesis and/or angiogenesis during early development of Xenopus embryos. However, the function of RasGRP2 in human vascular endothelium remains unknown. Therefore we aimed to analyze the function of human RasGRP2 in vascular endothelial cells. RasGRP2 overexpression did not increase Ras activation...
May 2013: Cell Adhesion & Migration
W Xiao, Y Su, S Zhou, Ch Yi, G He, Y Liu, Y Qi
We have previously reported that mtHSV, a herpes simplex virus 1 (HSV-1) mutant with an inactivated gene for β-galactosidase, can efficiently lyse tumor but not normal cells. However, the mechanism of this selective oncolytic activity is so far unclear. In this study, using the phage display screening we identified the cellular protein binding to HSV-1 mutant (mtHSV) as (Ras guanyl releasing protein 2) Rasgrp2 which regulates the Ras signaling pathway. Rasgrp2 was found to bind directly to purified mtHSV as well as to mtHSV present within infected HeLa cells where it aggregated on the cell membrane...
2013: Acta Virologica
Minghua Zhu, Deirdre M Fuller, Weiguo Zhang
The RasGRP (Ras guanine nucleotide-releasing protein) family proteins are guanine nucleotide exchange factors that activate Ras GTPases, ultimately leading to MAPK activation and many cellular processes. The RasGRP family has four members. Published studies demonstrate that RasGRP1, RasGRP2, and RasGRP3 play critical roles in T cells, platelets, and B cells, respectively. RasGRP4 is highly expressed in mast cells. Although previous data suggest that it is important in mast cell development and function, the role of RasGRP4 in mast cells and allergic responses has not been clearly demonstrated...
March 9, 2012: Journal of Biological Chemistry
James C Stone
Ras guanyl nucleotide releasing proteins (RasGRPs) are guanyl nucleotide exchange factors that activate Ras and related GTPases such as Rap. Like Sos proteins, RasGRPs have a catalytic region composed of a Ras exchange motif (REM) and a CDC25 domain. RasGRPs also possess a pair of atypical EF hands that may bind calcium in vivo and a C1 domain resembling the diacylglycerol (DAG)-binding domain of protein kinase C. DAG directly activates RasGRPs by a membrane recruitment mechanism as well as indirectly by PKC-mediated phosphorylation...
March 2011: Genes & Cancer
Anika Stadtmann, Laura Brinkhaus, Helena Mueller, Jan Rossaint, Matteo Bolomini-Vittori, Wolfgang Bergmeier, Hugo Van Aken, Denisa D Wagner, Carlo Laudanna, Klaus Ley, Alexander Zarbock
Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin αLβ2-mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)γ2-dependent and a separate PI3Kγ-dependent pathway. E-selectin-signaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLCγ2 (Plcg2) to αLβ2-activation is unknown. To identify this pathway, we used different Tat-fusion-mutants and gene-deficient mice in intravital microscopy, autoperfused flow chamber, peritonitis, and biochemical studies...
July 2011: European Journal of Immunology
Moritz Stolla, Lucia Stefanini, R Claire Roden, Massiel Chavez, Jessica Hirsch, Teshell Greene, Timothy D Ouellette, Sean F Maloney, Scott L Diamond, Mortimer Poncz, Donna S Woulfe, Wolfgang Bergmeier
Two major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbβ3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice...
January 20, 2011: Blood
Kentaro Nagamine, Akira Matsuda, Takamitsu Hori
Ras guanyl nucleotide-releasing protein 2 (RASGRP2) is a calcium- and diacylglycerol-responsive guanine nucleotide exchange factor. Previously, we reported that XRASGRP2, a homolog of human RASGRP2, is expressed in the vascular region of the Xenopus embryo during embryogenesis. Here, we report the regulatory mechanisms of human rasgrp2 gene expression in vascular endothelial cells. Although three alternative splicing variants, differing in the first exon of 5'-untranslated region (5'-UTR), have been found for the human rasgrp2 gene, reverse transcription-polymerase chain reaction (RT-PCR) showed that the cDNA containing the distal first exon (D1E) was expressed only in human umbilical artery endothelial cells...
2010: Biological & Pharmaceutical Bulletin
Lucia Stefanini, Wolfgang Bergmeier
Rapid activation of platelets at sites of vascular injury is a critical event in thrombosis and hemostasis. Here, we review recent findings, which (a) identified CalDAG-GEFI (RasGRP2) at the nexus of the rapid Ca(2+)-dependent platelet activation, (b) demonstrated a complex synergy between signaling provided by CalDAG-GEFI, protein kinase C and the Gi-coupled receptor for ADP, P2Y12, and (c) suggested CalDAG-GEFI as a novel target for anti-platelet therapy.
2010: Platelets
Kan Suzuki, Shuji Takahashi, Yoshikazu Haramoto, Yasuko Onuma, Kentaro Nagamine, Koji Okabayashi, Kohei Hashizume, Tadashi Iwanaka, Makoto Asashima
Ras guanyl nucleotide-releasing protein 2 (RASGRP2), one of the Ras guanine exchange factors, is implicated as a critical regulator of inside-out integrin activation in human lymphocytes, neutrophils and platelets. However, the activities of this protein in endothelial cells remain unclear. In the current study, we identify a physiological function in blood vessel formation for XRASGRP2, which is the Xenopus ortholog of mammalian RASGRP2. XRASGRP2 over-expression induced ectopic vascular formation, and XRASGRP2-knockdown embryos showed delayed vascular development...
2010: International Journal of Developmental Biology
Lena Svensson, Kimberley Howarth, Alison McDowall, Irene Patzak, Rachel Evans, Siegfried Ussar, Markus Moser, Ayse Metin, Mike Fried, Ian Tomlinson, Nancy Hogg
Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections...
March 2009: Nature Medicine
Lin Yang, Li Zhang, Qiuyu Wu, Douglas D Boyd
We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif...
December 12, 2008: Journal of Biological Chemistry
Kentaro Nagamine, Akira Matsuda, Makoto Asashima, Takamitsu Hori
Previously, we described the DNA microarray screening of vascular endothelial cells that were formed by treatment of aggregates prepared from Xenopus animal cap cells with activin and angiopoietin-2. One of the genes identified in this screening showed homology to human RASGRP2 which plays a role in the regulation of GTP-GDP exchange of the Ras and Rap proteins, and was named XRASGRP2. In the present study, we analyzed the expression pattern of xrasgrp2 during Xenopus embryogenesis. The xrasgrp2 mRNA was expressed after stage 24, as assessed by stage PCR analysis...
August 8, 2008: Biochemical and Biophysical Research Communications
Joanne E Johnson, Rebecca E Goulding, Ziwei Ding, Amir Partovi, Kira V Anthony, Nadine Beaulieu, Ghazaleh Tazmini, Rosemary B Cornell, Robert J Kay
RasGRPs (guanine-nucleotide-releasing proteins) are exchange factors for membrane-bound GTPases. All RasGRP family members contain C1 domains which, in other proteins, bind DAG (diacylglycerol) and thus mediate the proximal signal-transduction events induced by this lipid second messenger. The presence of C1 domains suggests that all RasGRPs could be regulated by membrane translocation driven by C1-DAG interactions. This has been demonstrated for RasGRP1 and RasGRP3, but has not been tested directly for RasGRP2, RasGRP4alpha and RasGRP4beta...
September 1, 2007: Biochemical Journal
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