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https://www.readbyqxmd.com/read/28912101/importance-of-the-rem-ras-exchange-domain-for-membrane-interactions-by-rasgrp3
#1
Agnes Czikora, Noemi Kedei, Heather Kalish, Peter M Blumberg
RasGRP comprises a family of guanine nucleotide exchange factors, regulating the dissociation of GDP from Ras GTPases to enhance the formation of the active GTP-bound form. RasGRP1 possesses REM (Ras exchange), GEF (catalytic), EF-hand, C1, SuPT (suppressor of PT), and PT (plasma membrane-targeting) domains, among which the C1 domain drives membrane localization in response to diacylglycerol or phorbol ester and the PT domain recognizes phosphoinositides. The homologous family member RasGRP3 shows less plasma membrane localization...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28822832/combined-immunodeficiency-with-ebv-positive-b-cell-lymphoma-and-epidermodysplasia-verruciformis-due-to-a-novel-homozygous-mutation-in-rasgrp1
#2
Craig D Platt, Ari J Fried, Rodrigo Hoyos-Bachiloglu, G Naheed Usmani, Birgitta Schmidt, Jennifer Whangbo, Roberto Chiarle, Janet Chou, Raif S Geha
RASGRP1 is a guanine-nucleotide-exchange factor essential for MAP-kinase mediated signaling in lymphocytes. We report the second case of RASGRP1 deficiency in a patient with a homozygous nonsense mutation in the catalytic domain of the protein. The patient had epidermodysplasia verruciformis, suggesting a clinically important intrinsic T cell function defect. Like the previously described patient, our proband also presented with CD4(+) T cell lymphopenia, impaired T cell proliferation to mitogens and antigens, reduced NK cell function, and EBV-associated lymphoma...
August 16, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28652304/thymic-progenitors-of-tcr%C3%AE-%C3%AE-cd8%C3%AE-%C3%AE-intestinal-intraepithelial-lymphocytes-require-rasgrp1-for-development
#3
Dominic P Golec, Romy E Hoeppli, Laura M Henao Caviedes, Jillian McCann, Megan K Levings, Troy A Baldwin
Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCRαβ(+)CD8αα intraepithelial lymphocyte (IEL) progenitors (IELps), even though both outcomes require strong TCR signaling...
August 7, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28392275/exploring-the-influence-of-indololactone-structure-on-selectivity-for-binding-to-the-c1-domains-of-pkc%C3%AE-pkc%C3%AE%C2%B5-and-rasgrp
#4
Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E Lewin, Lia C Garcia, Christopher C Lai, James A Kelley, Megan L Peach, Peter M Blumberg, María J Comin
C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins...
June 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28339466/in-silico-search-for-modifier-genes-associated-with-pancreatic-and-liver-disease-in-cystic-fibrosis
#5
Pascal Trouvé, Emmanuelle Génin, Claude Férec
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes...
2017: PloS One
https://www.readbyqxmd.com/read/27902448/rasgrp1-promotes-amphetamine-induced-motor-behavior-through-a-rhes-interaction-network-rhesactome-in-the-striatum
#6
Neelam Shahani, Supriya Swarnkar, Vincenzo Giovinazzo, Jenny Morgenweck, Laura M Bohn, Catherina Scharager-Tapia, Bruce Pascal, Pablo Martinez-Acedo, Kshitij Khare, Srinivasa Subramaniam
The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa-induced dyskinesia, and has a role in striatal motor control...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27891502/diacylglycerol-kinases-in-t-cell-tolerance-and-effector-function
#7
REVIEW
Shelley S Chen, Zhiming Hu, Xiao-Ping Zhong
Diacylglycerol kinases (DGKs) are a family of enzymes that regulate the relative levels of diacylglycerol (DAG) and phosphatidic acid (PA) in cells by phosphorylating DAG to produce PA. Both DAG and PA are important second messengers cascading T cell receptor (TCR) signal by recruiting multiple effector molecules, such as RasGRP1, PKCθ, and mTOR. Studies have revealed important physiological functions of DGKs in the regulation of receptor signaling and the development and activation of immune cells. In this review, we will focus on recent progresses in our understanding of two DGK isoforms, α and ζ, in CD8 T effector and memory cell differentiation, regulatory T cell development and function, and invariant NKT cell development and effector lineage differentiation...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27890930/histone-deacetylase-inhibitors-interrupt-hsp90%C3%A2-rasgrp1-and-hsp90%C3%A2-craf-interactions-to-upregulate-bim-and-circumvent-drug-resistance-in-lymphoma-cells
#8
H Ding, K L Peterson, C Correia, B Koh, P A Schneider, G S Nowakowski, S H Kaufmann
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo...
July 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27878761/genome-wide-association-analysis-of-the-sense-of-smell-in-u-s-older-adults-identification-of-novel-risk-loci-in-african-americans-and-european-americans
#9
Jing Dong, Annah Wyss, Jingyun Yang, T Ryan Price, Aude Nicolas, Michael Nalls, Greg Tranah, Nora Franceschini, Zongli Xu, Claudia Schulte, Alvaro Alonso, Steven R Cummings, Myriam Fornage, Dmitri Zaykin, Leping Li, Xuemei Huang, Stephen Kritchevsky, Yongmei Liu, Thomas Gasser, Robert S Wilson, Philip L De Jager, Andrew B Singleton, Jayant M Pinto, Tamara Harris, Thomas H Mosley, David A Bennett, Stephanie London, Lei Yu, Honglei Chen
The human sense of smell decreases with age, and a poor sense of smell are among the most important prodromal symptoms of several neurodegenerative diseases. Recent evidence further suggests a racial difference in the sense of smell among U.S. older adults. However, no genome-wide association study (GWAS) on the sense of smell has been conducted in African-Americans (AAs). We performed the first genome-wide meta-analysis of the sense of smell among 1979 AAs and 6582 European-Americans (EAs) from three U.S. aging cohorts...
November 23, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27804980/novel-identified-associations-of-rgs1-and-rasgrp1-variants-in-iga-nephropathy
#10
Xu-Jie Zhou, Swapan K Nath, Yuan-Yuan Qi, Celi Sun, Ping Hou, Yue-Miao Zhang, Ji-Cheng Lv, Su-Fang Shi, Li-Jun Liu, Ruoyan Chen, Wanling Yang, Kevin Zhi He, Yanming Li, Hong Zhang
Known susceptibility loci together can only explain about 6-8% of the disease heritability of IgA nephropathy (IgAN), suggesting that there are still a large number of genetic variants remained to be discovered. We previously identified IgAN and systemic lupus erythematosus (SLE)/lupus nephritis (LN) shared many loci based on GWAS on Chinese populations. The more recent study with high-density genotyping of immune-related loci in individuals with Asian ancestry identified 10 new and 6 suggestive loci in SLE...
November 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27776107/rasgrp1-deficiency-causes-immunodeficiency-with-impaired-cytoskeletal-dynamics
#11
Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, Emily M Mace, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P Banerjee, Papiya Sinha, Fabienne McClanahan, Gerhard J Zlabinger, Winfried F Pickl, John G Gribben, Hannes Stockinger, Keiryn L Bennett, Johannes B Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt, Ilhan Tezcan, Jordan S Orange, Kaan Boztug
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27465532/rasgrp1-and-rasgrp3-are-required-for-efficient-generation-of-early-thymic-progenitors
#12
Dominic P Golec, Laura M Henao Caviedes, Troy A Baldwin
T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27344389/association-analysis-for-feet-and-legs-disorders-with-whole-genome-sequence-variants-in-3-dairy-cattle-breeds
#13
Xiaoping Wu, Bernt Guldbrandtsen, Mogens Sandø Lund, Goutam Sahana
Identification of genetic variants associated with feet and legs disorders (FLD) will aid in the genetic improvement of these traits by providing knowledge on genes that influence trait variations. In Denmark, FLD in cattle has been recorded since the 1990s. In this report, we used deregressed breeding values as response variables for a genome-wide association study. Bulls (5,334 Danish Holstein, 4,237 Nordic Red Dairy Cattle, and 1,180 Danish Jersey) with deregressed estimated breeding values were genotyped with the Illumina Bovine 54k single nucleotide polymorphism (SNP) genotyping array...
September 2016: Journal of Dairy Science
https://www.readbyqxmd.com/read/27279372/autoantibody-mediated-pulmonary-alveolar-proteinosis-in-rasgrp1-deficient-mice
#14
Andrew Ferretti, Jarrod R Fortwendel, Sarah A Gebb, Robert A Barrington
Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome caused by the accumulation of surfactants in the alveoli. The most prevalent clinical form of PAP is autoimmune PAP (aPAP) whereby IgG autoantibodies neutralize GM-CSF. GM-CSF is a pleiotropic cytokine that promotes the differentiation, survival, and activation of alveolar macrophages, the cells responsible for surfactant degradation. IgG-mediated neutralization of GM-CSF thereby inhibits alveolar macrophage homeostasis and function, leading to surfactant accumulation and innate immunodeficiency...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27268232/association-of-established-thyroid-peroxidase-autoantibody-tpoab-genetic-variants-with-hashimoto-s-thyroiditis
#15
Luka Brčić, Ana Barić, Sanda Gračan, Dubravka Brdar, Vesela Torlak Lovrić, Nikolina Vidan, Tatijana Zemunik, Ozren Polašek, Maja Barbalić, Ante Punda, Vesna Boraska Perica
Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development. A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study...
November 2016: Autoimmunity
https://www.readbyqxmd.com/read/27183569/cd275-independent-il-17-producing-t-follicular-helper-like-cells-in-lymphopenic-autoimmune-prone-mice
#16
Christopher Smith, Janet E Buhlmann, Xiaogan Wang, Amber Bartlett, Bing Lim, Robert A Barrington
T cells undergo homeostatic expansion and acquire an activated phenotype in lymphopenic microenvironments. Restoration of normal lymphocyte numbers typically re-establishes normal homeostasis, and proinflammatory cytokine production returns to baseline. Mice deficient in guanine nucleotide exchange factor RasGRP1 exhibit dysregulated homeostatic expansion, which manifests as lymphoproliferative disease with autoantibody production. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development, as well as during germinal center responses, suggesting that T cell-independent and T cell-dependent mechanisms are responsible...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27159504/distinct-oncogenic-ras-signals-characterized-by-profound-differences-in-flux-through-the-rasgdp-rasgtp-cycle
#17
Marsilius Mues, Jeroen P Roose
T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive bone marrow cancer in children and adults, and chemotherapy often fails for relapsing patients. Molecularly targeted therapy is hindered by heterogeneity in T-ALL and mechanistic details of the affected pathways in T-ALL are needed. Deregulation of Ras signals is common in T-ALL. Ras is genetically mutated to a constitutively active form in about 15% of all haematopoietic malignancies, but there is a range of other ways to augment signaling through the Ras pathway...
January 2, 2017: Small GTPases
https://www.readbyqxmd.com/read/27022025/structural-basis-for-the-failure-of-the-c1-domain-of-ras-guanine-nucleotide-releasing-protein-2-rasgrp2-to-bind-phorbol-ester-with-high-affinity
#18
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
https://www.readbyqxmd.com/read/26939566/genetic-variants-associated-with-rheumatoid-arthritis-patients-and-serotypes-in-european-populations
#19
Otsanda Ruiz-Larrañaga, Maria Uribarri, Maria C Alcaro, Sergio Escorza-Treviño, Jokin Del Amo, Mikel Iriondo, Carmen Manzano, Paola Migliorini, Veronika Lóránd, Andone Estonba
OBJECTIVES: To replicate the association of rheumatoid arthritis (RA) susceptibility loci in an independent European sample and to assess their specificity with anti-citrullinated protein antibodies (ACPA) status. METHODS: A selection of 64 SNP previously associated with RA have been typed in a cohort of 267 RA patients (169 ACPA-positive and 98 ACPA-negative) and 152 controls from the Rheumatology Units of the University Hospital of Pisa (Italy) and the University of Pécs Medical Center (Hungary)...
March 2016: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/26851222/rasgrp1-is-an-essential-signaling-molecule-for-development-of-b1a-cells-with-autoantigen-receptors
#20
Benchang Guo, Thomas L Rothstein
B1a cells, particularly the PD-L2(+) B1a cell subset, are enriched with autoantigen-specific receptors. However, the underlying molecular mechanism responsible for the skewed selection of autoreactive B1a cells remains unclear. In this study, we find that B1 cells express only Ras guanyl nucleotide-releasing protein (RasGRP) 1, whereas B2 cells express mostly RasGRP3 and little RasGRP1. RasGRP1 is indispensable for transduction of weak signals. RasGRP1 deficiency markedly impairs B1a cell development and reduces serum natural IgM production; in particular, B1a cells that express autoantigen receptors, such as anti-phosphatidylcholine B1a cells, are virtually eliminated...
March 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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