ALBERT

Description: The early events during infection with an immunodeficiency virus were followed by application of pathogenic simian immunodeficiency virus atraumatically to the tonsils of macaques. Analyses by virologic assays and in situ hybridization revealed that the infection started locally in the tonsils, a mucosal-associated lymphoid organ, and quickly spread to other lymphoid tissues. At day 3, there were few infected cells, but then the number increased rapidly, reaching a high plateau between days 4 and 7. The infection was not detected in the dendritic cell-rich squamous epithelium to which the virus was applied; instead, it was primarily in CD4+ tonsillar T cells, close to the specialized antigen-transporting epithelium of the tonsillar crypts. Transport of the virus and immune-activating stimuli across this epithelium would allow mucosal lymphoid tissue to function in the atraumatic transmission of immunodeficiency viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stahl-Hennig, C -- Steinman, R M -- Tenner-Racz, K -- Pope, M -- Stolte, N -- Matz-Rensing, K -- Grobschupff, G -- Raschdorff, B -- Hunsmann, G -- Racz, P -- AI 40874/AI/NIAID NIH HHS/ -- AI 40877/AI/NIAID NIH HHS/ -- AI 42129/AI/NIAID NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Aug 20;285(5431):1261-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉German Primate Center, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10455052" target="_blank"〉PubMed〈/a〉

Description: A mechanism by which members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor cytokine family regulate gliogenesis in the developing mammalian central nervous system was characterized. Activation of the CNTF receptor promoted differentiation of cerebral cortical precursor cells into astrocytes and inhibited differentiation of cortical precursors along a neuronal lineage. Although CNTF stimulated both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Ras-mitogen-activated protein kinase signaling pathways in cortical precursor cells, the JAK-STAT signaling pathway selectively enhanced differentiation of these precursors along a glial lineage. These findings suggest that cytokine activation of the JAK-STAT signaling pathway may be a mechanism by which cell fate is controlled during mammalian development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonni, A -- Sun, Y -- Nadal-Vicens, M -- Bhatt, A -- Frank, D A -- Rozovsky, I -- Stahl, N -- Yancopoulos, G D -- Greenberg, M E -- NIHP30-HD 18655/HD/NICHD NIH HHS/ -- R01 CA43855/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1997 Oct 17;278(5337):477-83.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9334309" target="_blank"〉PubMed〈/a〉

Description: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of 〉100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating approximately 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944098/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Yukinori -- Wu, Di -- Trynka, Gosia -- Raj, Towfique -- Terao, Chikashi -- Ikari, Katsunori -- Kochi, Yuta -- Ohmura, Koichiro -- Suzuki, Akari -- Yoshida, Shinji -- Graham, Robert R -- Manoharan, Arun -- Ortmann, Ward -- Bhangale, Tushar -- Denny, Joshua C -- Carroll, Robert J -- Eyler, Anne E -- Greenberg, Jeffrey D -- Kremer, Joel M -- Pappas, Dimitrios A -- Jiang, Lei -- Yin, Jian -- Ye, Lingying -- Su, Ding-Feng -- Yang, Jian -- Xie, Gang -- Keystone, Ed -- Westra, Harm-Jan -- Esko, Tonu -- Metspalu, Andres -- Zhou, Xuezhong -- Gupta, Namrata -- Mirel, Daniel -- Stahl, Eli A -- Diogo, Dorothee -- Cui, Jing -- Liao, Katherine -- Guo, Michael H -- Myouzen, Keiko -- Kawaguchi, Takahisa -- Coenen, Marieke J H -- van Riel, Piet L C M -- van de Laar, Mart A F J -- Guchelaar, Henk-Jan -- Huizinga, Tom W J -- Dieude, Philippe -- Mariette, Xavier -- Bridges, S Louis Jr -- Zhernakova, Alexandra -- Toes, Rene E M -- Tak, Paul P -- Miceli-Richard, Corinne -- Bang, So-Young -- Lee, Hye-Soon -- Martin, Javier -- Gonzalez-Gay, Miguel A -- Rodriguez-Rodriguez, Luis -- Rantapaa-Dahlqvist, Solbritt -- Arlestig, Lisbeth -- Choi, Hyon K -- Kamatani, Yoichiro -- Galan, Pilar -- Lathrop, Mark -- RACI consortium -- GARNET consortium -- Eyre, Steve -- Bowes, John -- Barton, Anne -- de Vries, Niek -- Moreland, Larry W -- Criswell, Lindsey A -- Karlson, Elizabeth W -- Taniguchi, Atsuo -- Yamada, Ryo -- Kubo, Michiaki -- Liu, Jun S -- Bae, Sang-Cheol -- Worthington, Jane -- Padyukov, Leonid -- Klareskog, Lars -- Gregersen, Peter K -- Raychaudhuri, Soumya -- Stranger, Barbara E -- De Jager, Philip L -- Franke, Lude -- Visscher, Peter M -- Brown, Matthew A -- Yamanaka, Hisashi -- Mimori, Tsuneyo -- Takahashi, Atsushi -- Xu, Huji -- Behrens, Timothy W -- Siminovitch, Katherine A -- Momohara, Shigeki -- Matsuda, Fumihiko -- Yamamoto, Kazuhiko -- Plenge, Robert M -- 20385/Arthritis Research UK/United Kingdom -- 79321/Canadian Institutes of Health Research/Canada -- K08-KAR055688A/PHS HHS/ -- K24 AR052403/AR/NIAMS NIH HHS/ -- P60 AR047785/AR/NIAMS NIH HHS/ -- R01 AR056768/AR/NIAMS NIH HHS/ -- R01 AR057108/AR/NIAMS NIH HHS/ -- R01 AR059648/AR/NIAMS NIH HHS/ -- R01 AR063759/AR/NIAMS NIH HHS/ -- R01-AR056291/AR/NIAMS NIH HHS/ -- R01-AR056768/AR/NIAMS NIH HHS/ -- R01-AR057108/AR/NIAMS NIH HHS/ -- R01-AR059648/AR/NIAMS NIH HHS/ -- R01-AR065944/AR/NIAMS NIH HHS/ -- R01AR063759-01A1/AR/NIAMS NIH HHS/ -- R21 AR056042/AR/NIAMS NIH HHS/ -- T15 LM007450/LM/NLM NIH HHS/ -- U01 GM092691/GM/NIGMS NIH HHS/ -- U01-GM092691/GM/NIGMS NIH HHS/ -- U19 HL065962/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):376-81. doi: 10.1038/nature12873. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. [5] Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia. ; 1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan. ; Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; New York University Hospital for Joint Diseases, New York, New York 10003, USA. ; Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA. ; Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. ; Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. ; 1] University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. [2] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada. ; Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada. ; Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [2] Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. ; School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China. ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands. ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] Service de Rhumatologie et INSERM U699 Hopital Bichat Claude Bernard, Assistance Publique des Hopitaux de Paris, Paris 75018, France. [2] Universite Paris 7-Diderot, Paris 75013, France. ; Institut National de la Sante et de la Recherche Medicale (INSERM) U1012, Universite Paris-Sud, Rhumatologie, Hopitaux Universitaires Paris-Sud, Assistance Publique-Hopitaux de Paris (AP-HP), Le Kremlin Bicetre 94275, France. ; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. ; 1] Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. [2] GlaxoSmithKline, Stevenage SG1 2NY, UK. [3] University of Cambridge, Cambridge CB2 1TN, UK. ; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea. ; Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain. ; Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain. ; Hospital Clinico San Carlos, Madrid 28040, Spain. ; 1] Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. [2] Department of Rheumatology, Umea University, Umea SE-901 87, Sweden. ; 1] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA. [2] Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [3] Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Centre d'Etude du Polymorphisme Humain (CEPH), Paris 75010, France. ; Universite Paris 13 Sorbonne Paris Cite, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France. ; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 0G1 Canada. ; 1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. [2] National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. ; Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. ; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA. ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan. ; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. ; Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden. ; The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; 1] Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA. [2] Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA. ; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. ; Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. [3] Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; 1] Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. [2] Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390342" target="_blank"〉PubMed〈/a〉

Description: Adenosine diphosphate-ribosylation factor 6 (ARF6), ARF6 mutants, and ARF1 were transiently expressed in Chinese hamster ovary cells, and the effects on receptor-mediated endocytosis were assessed. Overexpressed ARF6 localized to the cell periphery and led to a redistribution of transferrin receptors to the cell surface and a decrease in the rate of uptake of transferrin. Similar results were obtained when a mutant defective in guanosine triphosphate hydrolysis was expressed. Expression of a dominant negative mutant, ARF6(T27N), resulted in an intracellular distribution of transferrin receptors and an inhibition of transferrin recycling to the cell surface. In contrast, overexpression of ARF1 had little or no effect on these parameters of endocytosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉D'Souza-Schorey, C -- Li, G -- Colombo, M I -- Stahl, P D -- New York, N.Y. -- Science. 1995 Feb 24;267(5201):1175-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7855600" target="_blank"〉PubMed〈/a〉

Description: Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stahl, N -- Farruggella, T J -- Boulton, T G -- Zhong, Z -- Darnell, J E Jr -- Yancopoulos, G D -- New York, N.Y. -- Science. 1995 Mar 3;267(5202):1349-53.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7871433" target="_blank"〉PubMed〈/a〉

Description: Some growth factors are therapeutically useful partly because restricted expression of their receptors limits their action to particular cell types. However, no unique stimulatory factor is known for many clinically relevant cell types, such as CD34+ hematopoietic stem cells. Here, soluble alpha receptor (R alpha) components for interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) were targeted in an active form to cells expressing surface markers such as CD34 or CD45, thereby rendering those cells responsive to IL-6 or CNTF. The targeting of R alpha components may provide the means to create "designer" cytokines that activate a desired cell type expressing a specific cell surface marker.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Economides, A N -- Ravetch, J V -- Yancopoulos, G D -- Stahl, N -- New York, N.Y. -- Science. 1995 Nov 24;270(5240):1351-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7481821" target="_blank"〉PubMed〈/a〉

Description: The alpha component of the receptor for ciliary neurotrophic factor (CNTF) differs from other known growth factor receptors in that it is anchored to cell membranes by a glycosylphosphatidylinositol linkage. One possible function of this type of linkage is to allow for the regulated release of this receptor component. Cell lines not normally responsive to CNTF responded to treatment with a combination of CNTF and a soluble form of the CNTF alpha receptor component. These findings not only demonstrate that the CNTF receptor alpha chain is a required component of the functional CNTF receptor complex but also reveal that it can function in soluble form as part of a heterodimeric ligand. Potential physiological roles for the soluble CNTF receptor are suggested by its presence in cerebrospinal fluid and by its release from skeletal muscle in response to peripheral nerve injury.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, S -- Aldrich, T H -- Ip, N Y -- Stahl, N -- Scherer, S -- Farruggella, T -- DiStefano, P S -- Curtis, R -- Panayotatos, N -- Gascan, H -- New York, N.Y. -- Science. 1993 Mar 19;259(5102):1736-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7681218" target="_blank"〉PubMed〈/a〉

Description: The ciliary neurotrophic factor (CNTF) receptor complex is shown here to include the CNTF binding protein (CNTFR alpha) as well as the components of the leukemia inhibitory factor (LIF) receptor, LIFR beta (the LIF binding protein) and gp130 [the signal transducer of interleukin-6 (IL-6)]. Thus, the conversion of a bipartite LIF receptor into a tripartite CNTF receptor apparently occurs by the addition of the specificity-conferring element CNTFR alpha. Both CNTF and LIF trigger the association of initially separate receptor components, which in turn results in tyrosine phosphorylation of receptor subunits. Unlike the IL-6 receptor complex in which homodimerization of gp130 appears to be critical for signal initiation, signaling by the CNTF and LIF receptor complexes depends on the heterodimerization of gp130 with LIFR beta. Ligand-induced dimerization of signal-transducing receptor components, also seen with receptor tyrosine kinases, may provide a general mechanism for the transmission of a signal across the cell membrane.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, S -- Aldrich, T H -- Stahl, N -- Pan, L -- Taga, T -- Kishimoto, T -- Ip, N Y -- Yancopoulos, G D -- New York, N.Y. -- Science. 1993 Jun 18;260(5115):1805-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8390097" target="_blank"〉PubMed〈/a〉

Description: The three-dimensional solution structure of a complex between the DNA binding domain of the chicken erythroid transcription factor GATA-1 and its cognate DNA site has been determined with multidimensional heteronuclear magnetic resonance spectroscopy. The DNA binding domain consists of a core which contains a zinc coordinated by four cysteines and a carboxyl-terminal tail. The core is composed of two irregular antiparallel beta sheets and an alpha helix, followed by a long loop that leads into the carboxyl-terminal tail. The amino-terminal part of the core, including the helix, is similar in structure, although not in sequence, to the amino-terminal zinc module of the glucocorticoid receptor DNA binding domain. In the other regions, the structures of these two DNA binding domains are entirely different. The DNA target site in contact with the protein spans eight base pairs. The helix and the loop connecting the two antiparallel beta sheets interact with the major groove of the DNA. The carboxyl-terminal tail, which is an essential determinant of specific binding, wraps around into the minor groove. The complex resembles a hand holding a rope with the palm and fingers representing the protein core and the thumb, the carboxyl-terminal tail. The specific interactions between GATA-1 and DNA in the major groove are mainly hydrophobic in nature, which accounts for the preponderance of thymines in the target site. A large number of interactions are observed with the phosphate backbone.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Omichinski, J G -- Clore, G M -- Schaad, O -- Felsenfeld, G -- Trainor, C -- Appella, E -- Stahl, S J -- Gronenborn, A M -- New York, N.Y. -- Science. 1993 Jul 23;261(5120):438-46.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8332909" target="_blank"〉PubMed〈/a〉

Description: A recently defined family of cytokines, consisting of ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), and interleukin-6 (IL-6), utilize the Jak-Tyk family of cytoplasmic tyrosine kinases. The beta receptor components for this cytokine family, gp130 and LIF receptor beta, constitutively associate with Jak-Tyk kinases. Activation of these kinases occurs as a result of ligand-induced dimerization of the receptor beta components. Unlike other cytokine receptors studied to date, the receptors for the CNTF cytokine family utilize all known members of the Jak-Tyk family, but induce distinct patterns of Jak-Tyk phosphorylation in different cell lines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stahl, N -- Boulton, T G -- Farruggella, T -- Ip, N Y -- Davis, S -- Witthuhn, B A -- Quelle, F W -- Silvennoinen, O -- Barbieri, G -- Pellegrini, S -- P30 CA21765/CA/NCI NIH HHS/ -- R01 DK42932/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 1994 Jan 7;263(5143):92-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8272873" target="_blank"〉PubMed〈/a〉