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Li-Xin Wang, Yang Li, Guan-Zhi Chen
Metastatic melanoma is an aggressive skin cancer and is one of the global malignancies with high mortality and morbidity. It is essential to identify and verify diagnostic biomarkers of early metastatic melanoma. Previous studies have systematically assessed protein biomarkers and mRNA-based expression characteristics. However, molecular markers for the early diagnosis of metastatic melanoma have not been identified. To explore potential regulatory targets, we have analyzed the gene microarray expression profiles of malignant melanoma samples by co-expression analysis based on the network approach...
2018: PloS One
José M Bastida, María L Lozano, Rocío Benito, Kamila Janusz, Verónica Palma-Barqueros, Mónica Del Rey, Jesús M Hernández-Sánchez, Susana Riesco, Nuria Bermejo, Hermenegildo González-García, Agustín Rodriguez-Alén, Carlos Aguilar, Teresa Sevivas, María F López-Fernández, Anna E Marneth, Bert A van der Reijden, Neil V Morgan, Steve P Watson, Vicente Vicente, Jesús M Hernández-Rivas, José Rivera, José R González-Porras
Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders...
January 2018: Haematologica
Yvonne Vercoulen, Yasushi Kondo, Jeffrey S Iwig, Axel B Janssen, Katharine A White, Mojtaba Amini, Diane L Barber, John Kuriyan, Jeroen P Roose
RasGRPs are guanine nucleotide exchange factors that are specific for Ras or Rap, and are important regulators of cellular signaling. Aberrant expression or mutation of RasGRPs results in disease. An analysis of RasGRP1 SNP variants led to the conclusion that the charge of His 212 in RasGRP1 alters signaling activity and plasma membrane recruitment, indicating that His 212 is a pH sensor that alters the balance between the inactive and active forms of RasGRP1. To understand the structural basis for this effect we compared the structure of autoinhibited RasGRP1, determined previously, to those of active RasGRP4:H-Ras and RasGRP2:Rap1b complexes...
September 27, 2017: ELife
Teresa Sevivas, José María Bastida, David S Paul, Eva Caparros, Verónica Palma-Barqueros, Margarida Coucelo, Dalila Marques, Francisca Ferrer-Marín, José Ramón González-Porras, Vicente Vicente, Jesús María Hernández-Rivas, Steve P Watson, María Luisa Lozano, Wolfgang Bergmeier, José Rivera
The RASGRP2 gene encodes the Ca(2+) and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), which plays a key role in integrin activation in platelets and neutrophils. We here report two new RASGRP2 variants associated with platelet dysfunction and bleeding in patients. The homozygous patients had normal platelet and neutrophil counts and morphology. Platelet phenotyping showed: prolonged PFA-100 closure times; normal expression of major glycoprotein receptors; severely reduced platelet aggregation response to ADP and collagen (both patients); aggregation response to PAR1 and arachidonic acid markedly impaired in one patient; PMA-induced aggregation unaffected; platelet secretion, clot retraction, and spreading minimally affected...
August 1, 2017: Platelets
Emilse Bermejo, Maria F Alberto, David S Paul, Aaron A Cook, Paquita Nurden, Analia Sanchez Luceros, Alan T Nurden, Wolfgang Bergmeier
Congenital platelet function disorders are often the result of defects in critical signal transduction pathways required for platelet adhesion and clot formation. Mutations affecting RASGRP2, the gene encoding the Rap GTPase activator, CalDAG-GEFI, give rise to a novel, and rare, group of platelet signal transduction abnormalities. We here report platelet function studies for two brothers (P1 and P2) expressing a novel variant of RASGRP2, CalDAG-GEFI(p.Gly305Asp). P1 and P2 have a lifelong history of bleeding with severe epistaxis successfully treated with platelet transfusions or rFVIIa...
January 2018: Platelets
Bi-Dar Wang, Kristin Ceniccola, SuJin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A Garcia-Blanco, Steven R Patierno, Norman H Lee
Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants...
June 30, 2017: Nature Communications
Sarah K Westbury, Matthias Canault, Daniel Greene, Emilse Bermejo, Katharine Hanlon, Michele P Lambert, Carolyn M Millar, Paquita Nurden, Samya G Obaji, Shoshana Revel-Vilk, Chris Van Geet, Kate Downes, Sofia Papadia, Salih Tuna, Christopher Watt, Kathleen Freson, Michael A Laffan, Willem H Ouwehand, Marie-Christine Alessi, Ernest Turro, Andrew D Mumford
Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2 , which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls...
August 24, 2017: Blood
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
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