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Roberts AE Araki T Swanson KD Montgomery KT Schiripo TA Joshi VA Li L Yassin Y Tamburino AM Neel BG Kucherlapati RS 《Nature genetics》2007,39(1):70-74
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation. 相似文献
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E Turpin J Wantyghem Y Neel DGoussault 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1978,286(4):363-366
Glycoproteins of the lymphocyte surface are involved in many membrane mediated events. Their specific carbohydrate determinants might interact with lectins. Purification of macromolecules released from normal human lymphocytes by trypsin was performed using gel filtration and affinity properties for Ricinus sanguineus agglutinin. Some structural and biochemical characteristics are given. Relation to HLA determinants and surface immunoglobulins is discussed. 相似文献
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The stimulation of a variety of cell surface receptors promotes the accumulation of the active, GTP-bound form of Ras proteins in cells. This is a critical step in signal transduction because inhibition of Ras activation by anti-Ras antibodies or dominant inhibitory Ras mutants blocks many of the effects of these receptors on cellular function. To reach the active GTP-bound state, Ras proteins must first release bound GDP. This rate-limiting step in GTP binding is thought to be catalysed by a guanine-nucleotide-releasing factor (GRF). Here we report the cloning of complementary DNAs from a rat brain library that encode a approximately 140K GRF for Ras p21 (p140Ras-GRF). Its carboxy-terminal region is similar to that of CDC25, a GRF for Saccharomyces cerevisiae RAS. This portion of Ras-GRF accelerated the release of GDP from RasH and RasN p21 in vitro, but not from the related RalA, or CDC42Hs GTP-binding proteins. A region in the amino-terminal end of Ras-GRF is similar to both the human breakpoint cluster protein, Bcr, and the dbl oncogene product, a guanine-nucleotide-releasing factor for CDC42Hs. An understanding of Ras-GRF function will enhance our knowledge of the many signal transduction pathways mediated by Ras proteins. 相似文献
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Van Heuverswyn F Li Y Neel C Bailes E Keele BF Liu W Loul S Butel C Liegeois F Bienvenue Y Ngolle EM Sharp PM Shaw GM Delaporte E Hahn BH Peeters M 《Nature》2006,444(7116):164
Chimpanzees (Pan troglodytes troglodytes) from west central Africa are recognized as the reservoir of simian immunodeficiency viruses (SIVcpzPtt) that have crossed at least twice to humans: this resulted in the AIDS pandemic (from human immunodeficiency virus HIV-1 group M) in one instance and infection of just a few individuals in Cameroon (by HIV-1 group N) in another. A third HIV-1 lineage (group O) from west central Africa also falls within the SIVcpzPtt radiation, but the primate reservoir of this virus has not been identified. Here we report the discovery of HIV-1 group O-like viruses in wild gorillas. 相似文献
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Essential role for Gab2 in the allergic response. 总被引:24,自引:0,他引:24
H Gu K Saito L D Klaman J Shen T Fleming Y Wang J C Pratt G Lin B Lim J P Kinet B G Neel 《Nature》2001,412(6843):186-190
Dos/Gab family scaffolding adapters (Dos, Gab1, Gab2) bind several signal relay molecules, including the protein-tyrosine phosphatase Shp-2 and phosphatidylinositol-3-OH kinase (PI(3)K); they are also implicated in growth factor, cytokine and antigen receptor signal transduction. Mice lacking Gab1 die during embryogenesis and show defective responses to several stimuli. Here we report that Gab2-/- mice are viable and generally healthy; however, the response (for example, degranulation and cytokine gene expression) of Gab2-/- mast cells to stimulation of the high affinity immunoglobulin-epsilon (IgE) receptor Fc(epsilon)RI is defective. Accordingly, allergic reactions such as passive cutaneous and systemic anaphylaxis are markedly impaired in Gab2-/- mice. Biochemical analyses reveal that signalling pathways dependent on PI(3)K, a critical component of Fc(epsilon)RI signalling, are defective in Gab2-/- mast cells. Our data identify Gab2 as the principal activator of PI(3)K in response to Fc(epsilon)RI activation, thereby providing genetic evidence that Dos/Gab family scaffolds regulate the PI(3)K pathway in vivo. Gab2 and/or its associated signalling molecules may be new targets for developing drugs to treat allergy. 相似文献
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STAT3 signalling is required for leptin regulation of energy balance but not reproduction 总被引:33,自引:0,他引:33
Bates SH Stearns WH Dundon TA Schubert M Tso AW Wang Y Banks AS Lavery HJ Haq AK Maratos-Flier E Neel BG Schwartz MW Myers MG 《Nature》2003,421(6925):856-859
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Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration 总被引:1,自引:0,他引:1
Gold B Merriam JE Zernant J Hancox LS Taiber AJ Gehrs K Cramer K Neel J Bergeron J Barile GR Smith RT;AMD Genetics Clinical Study Group Hageman GS Dean M Allikmets R 《Nature genetics》2006,38(4):458-462
Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histocompatibility complex class III region, for genetic variation in two independent cohorts comprising approximately 900 individuals with AMD and approximately 400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD. 相似文献
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R. D. Henson A. C. Thompson P. A. Hedin P. R. Nichols W. W. Neel 《Cellular and molecular life sciences : CMLS》1975,31(2):145-145
Zusammenfassung Isolierung und Strukturzuteilung für ein Alkaloid ausColeomegilla maculata (Coleoptera: Curculionidae).
Coleoptera: Curculionidae.
In cooperation with the Mississippi Agricultural and Forestry Experiment Station, Mississippi State, Mississippi 39762. Received for publication.
Mention of a proprietary product does not necessarily imply endorsement of this product by the USDA. 相似文献
Coleoptera: Curculionidae.
In cooperation with the Mississippi Agricultural and Forestry Experiment Station, Mississippi State, Mississippi 39762. Received for publication.
Mention of a proprietary product does not necessarily imply endorsement of this product by the USDA. 相似文献
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Chen B Bronson RT Klaman LD Hampton TG Wang JF Green PJ Magnuson T Douglas PS Morgan JP Neel BG 《Nature genetics》2000,24(3):296-299
Atrioventricular and semilunar valve abnormalities are common birth defects, but how cardiac valvulogenesis is directed remains largely unknown. During studies of genetic interaction between Egfr, encoding the epidermal growth factor receptor, and Ptpn11, encoding the protein-tyrosine-phosphatase Shp2, we discovered that Egfr is required for semilunar, but not atrioventricular, valve development. Although unnoticed in earlier studies, mice homozygous for the hypomorphic Egfr allele waved-2 (Egfrwa2/wa2) exhibit semilunar valve enlargement resulting from over-abundant mesenchymal cells. Egfr-/- mice (CD1 background) have similar defects. The penetrance and severity of the defects in Egfrwa2/wa2 mice are enhanced by heterozygosity for a targeted mutation of exon 2 of Ptpn11 (ref. 3). Compound (Egfrwa2/wa2:Ptpn11+/-) mutant mice also show premature lethality. Electrocardiography, echocardiography and haemodynamic analyses showed that affected mice develop aortic stenosis and regurgitation. Our results identify the Egfr and Shp2 as components of a growth-factor signalling pathway required specifically for semilunar valvulogenesis, support the hypothesis that Shp2 is required for Egfr signalling in vivo, and provide an animal model for aortic valve disease. 相似文献
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